The Biochemistry of Drug Metabolism - An Introduction

CHEMISTRY & BIODIVERSITY Vol.
5 (2008)
2171
REVIEW The Biochemistry of Drug Metabolism An Introduction

Part 4. Reactions of Conjugation and Their Enzymes
by Bernard Testa* a ) and Stefanie D. Krmer b )
a
) Department of Pharmacy, University Hospital Centre (CHUV), Rue du Bugnon, CH-1011 Lausanne (e-mail: Bernard.Testa@chuv.ch) b ) Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich
This Part 4 of our biochemical introduction to drug metabolism [1 4] presents the reactions of conjugation and their enzymes. As we shall see, reactions of conjugation are also a major focus of interest in the metabolism of drugs and other xenobiotics. Books specifically dedicated to conjugation reactions are rare [5], but much recent information can be found in book chapters (e.g., [6] [7]). For a reaction of conjugation to occur, a suitable functional group must be present in the substrate, which will serve as the anchoring site for an endogenous molecule or moiety such as CH3 , sulfate, glucuronic acid, or glutathione. Conjugation reactions are thus synthetic (i.e., anabolic) reactions whose products are of modestly to markedly higher molecular weight than the corresponding substrate. As for the anchoring group, it can either be present in a xenobiotic or be created by a functionalization reaction. In other words, reactions of conjugation are able to produce first-generation as well as later-generation metabolites. We, therefore, consider as unfelicitous the term of phase II reactions commonly used to designate conjugations. A first issue when discussing reactions of conjugation will be to offer a clear definition. As we shall see, a number of criteria exist, all of which show some degree of fuzziness, and only one of which must necessarily be met. This has indeed led to some confusion with reactions of hydrolysis, which some biochemists have viewed as conjugation. We oppose such a view for reasons previously explained [3]. To repeat what we stated, reactions of hydrolysis are not catalyzed by transferases (EC 2) but by hydrolases (EC 3) [8], and water is not an endogenously synthesized molecule or moiety linked covalently to a cofactor. Reactions of conjugation, like the reactions of functionalization we saw in Parts 2 and 3, act on exogenous substrates (i.e., xenobiotics [1]) as well as endogenous substrates (i.e., endobiotics). This dual functionality may create a potential for metabolic interaction between a drug and an endogenous substrate, a frequently overlooked mechanism of toxicity. Thus, there may be competitive affinity for the catalytic site of an endobiotic-metabolizing enzyme, or there may be competition for the limited supply of a cofactor. A typical example of the latter case is found with
2008 Verlag Helvetica Chimica Acta AG, Zrich
2172
CHEMISTRY & BIODIVERSITY Vol. 5 (2008)
paracetamol, a high-dose drug undergoing extensive glucuronidation whose administration is forbidden to neonates and babies, since it deprives them of the glucuronic acid they need to detoxify bilirubin.
2173
Fig. 4.1. The structure of this Part follows custom as much as logic. First, an introductory Chapter will present an overview of the reactions of conjugation, their criteria, and their similarities and differences with functionalization reactions. As for the major reactions to be discussed in the subsequent Chapters, there is no overwhelming argument for preferring one order over another. We shall begin with the rather straightforward case of the reactions of methylation (Chapt. 4.2). Reactions of sulfonation (Chapt. 4.3) and glucuronidation (Chapt. 4.4) sometimes compete for the same substrates and will, therefore, be treated in sequence. Together with sulfonation, we will have a few things to say about reactions of phosphorylation, whose rarity should not obscure their significance in the activation of some drugs. Chapt. 4.5 and 4.6 center on coenzyme A, but with a difference. Reactions of acetylation (Chapt. 4.5) follow the usual pattern in having the conjugating moiety carried by the coenzyme, here coenzyme A. In contrast, there is a variety of reactions where the substrate (be it a xenobiotic or an endobiotic) is coupled to coenzyme A prior to being processed along vastly different pathways (Chapt. 4.6). Chapt. 4.7 presents glutathione and its reactions, a topic of marked biocomplexity and great toxicological significance. A few unclassifiable reactions will be summarized in Chapt. 4.8.
2174
Fig. 4.2. This Figure is a slightly amended form of Fig. 1.12 we saw in Part 1 [1], with a few additional details. The focus here is on the conjugating moiety being transferred to the substrate as a result of a conjugation reaction. Reference is made to Chapt. 4.2 4.8 to help the readers get a better view of the present Part. We also have here a first glance at the different pathways which xenobiotic coenzyme A conjugates can follow. Two of these pathways are not conjugations stricto sensu and, for this reason, are written in italics. Nevertheless, they will be discussed here, since a coenzyme A conjugate is the indispensable intermediate. These two pathways are the unidirectional inversion of configuration of profens (and a few other xenobiotics) and the b-oxidation of fatty acid analogs. As for the reactions in Chapt. 4.8, they represent poorly investigated pathways nevertheless worthy of some attention.
2175
Fig. 4.3. Conjugation reactions are characterized by a number of criteria which are presented here [5] [6] [9]. First and above all, they involve an endogenous molecule (called the endogenous conjugating moiety, and sometimes abbreviated as the endocon) with which the substrate is coupled. This is the absolute criterion of conjugation reactions, although, as we shall see, there may be arbitrariness in deciding whether a conjugating moiety such as CO2 is endogenous. Second, this endogenous molecule or moiety is generally polar (hydrophilic) or even highly polar, but there are exceptions. Third, the size of the endocon is generally in the range of 100 300 Da. Fourth, the endogenous conjugating moiety is usually carried by a cofactor, with the chemical bond linking the cofactor and the endocon being a high-energy one such that the Gibbs energy released upon its cleavage drives the transfer of the endocon to the substrate. Fifth, conjugation reactions are catalyzed by enzymes known as transferases (EC 2) which bind the substrate and the cofactor in such a manner that their close proximity allows the reaction to proceed. The metaphor of transferases being a nuptial bed has not escaped some biochemists. It is important from a biochemical and practical viewpoint to note that Criteria 2 5 considered separately are neither sufficient nor necessary to define conjugation reactions. They are not sufficient, since, in hydrogenation reactions (i.e., typical reactions of oxidoreduction), the hydride is also transferred from a cofactor (NADPH or NADH). And they are not necessary, since they all suffer from some important exceptions (see next Figure).
2176
Fig. 4.4. This Figure summarizes in tabular form the cases of compliance and noncompliance to the five conjugation criteria. As can be seen, Criterion 1 is indeed the only one that knows no exception, since all conjugating moieties involved are indeed endogenous. Thus, the C2 unit in chain elongation is derived from acetyl-coenzyme A (Chapt. 4.6). Most of the CO2 used in the formation of carbamic acids (Chapt. 4.8) is clearly also produced in vivo. The criterion of polarity of the endocon (Criterion 2) knows only two major exceptions, namely the coupling of xenobiotic carboxylic acids to sterols or to diglycerides (to yield mixed triglycerides), and the C2 chain elongation (Chapt. 4.6). The transfer of a CH3 group is special, since it adds a hydrophobic moiety except when forming quaternary ammonium metabolites (Chapt. 4.2). The CH3 group, being small, is also an exception to Criterion 3 as is the acetyl moiety. But we also have relatively large endocons such as sterols (Chapt. 4.6) and glutathione (Chapt. 4.7). As for the conjugating moiety being carried by a coenzyme (Criterion 4), exceptions are glutathione (Chapt. 4.7), carbonyl compounds (Chapt. 4.8), and all reactions in Chapt. 4.6, since here and as stated it is the substrate rather than the endocon that is attached to coenzyme A. Finally, catalysis by a transferase (Criterion 5) is almost always the case, the few exceptions being the coupling of hydrazines with carbonyl compounds (Chapt. 4.8) and some nonenzymatic conjugations with glutathione (Chapt. 4.7).
2177
Fig. 4.5. This Figure and the next one illustrate the deep analogy between the physiological reactions of endobiotic conjugation and the conjugation of xenobiotics. Their graphical similarity with Fig. 1.23 in Part 1 [1] is not fortuitous. As shown here, a waste product of physiological metabolism (e.g., bilirubin, a toxic breakdown product of hemoglobin), an endogenous compound (e.g., the neurotransmitter noradrenaline), or a nutrient (e.g., a fatty acid) is captured by a transferase. The latter catalyzes the transfer of the adequate conjugating moiety from the cofactor to the substrate, yielding a conjugate. These reactions have evolved to fulfill a variety of functions, as classified in the Figure. Thus, the toxic bilirubin is detoxified by conjugation with glucuronic acid, the resulting glucuronide being excreted in the bile. The case of noradrenaline is different, being N-methylated to the neurotransmitter adrenaline or O-methylated to an inactive metabolite. The case of metabolic intermediates in anabolism (synthetic metabolism) and catabolism (breakdown metabolism) is illustrated with fatty acids, whose coenzyme A conjugates can undergo anabolism by C2 chain elongation, or catabolism by b-oxidation.
2178
Fig. 4.6. Reactions of xenobiotic conjugation have evolved from physiological conjugations to fulfill protective functions [10]. Thus, a xenobiotic containing an adequate target group, or a phase I metabolite, is captured and metabolized by a transferase. As we shall see, some transferases recognize endobiotics and xenobiotics alike (e.g., catechol O-methyltransferase), while others have diversified and are specialized to some extent toward endobiotics or xenobiotics (e.g., UDP-glucuronyltransferases). As a rule, drug conjugation inactivates the substrate, but there are only few noteworthy exceptions such as the highly active morphine 6-O-glucuronide. Similarly, toxicity is usually greatly decreased by conjugation (e.g., N-methylpyridinium), but, as we shall see, there are numerous examples of conjugations leading to toxification. Some conjugates may indeed be reactive (e.g., some acyl glucuronides), whereas others are highly lipophilic and may accumulate in tissues as residues (e.g., some mixed triglycerides). Such exceptions should not hide the fact that the greatly increased hydrophilicity of many conjugates relative to their parent compound facilitates their excretion. What is more, a co-evolution of transferases and transporters is believed to have occurred, such that the formation of polar conjugates (e.g., glucuronides and glutathione derivatives) is coupled to their active excretion [11].
2179
Fig. 4.7. This Figure opens Chapt. 4.2 dedicated to biomethylation. These reactions are catalyzed by methyltransferases (EC 2.1.1), and the endogenous conjugating moiety is a CH3 group carried by the cofactor S-adenosyl-l-methionine (4.1; SAM, AdoMet) [5 8] [12] [13]. The CH3 group in SAM is bound to a sulfonium center, giving it a marked electrophilic character and explaining its reactivity. During the reaction, S-adenosyl-lmethionine loses the CH3 group and the positive charge to become S-adenosyl-lhomocysteine (4.2). As shown in the Figure, three major types of reactions are recognized, namely the O-methylation of phenolic groups (mainly catechols), the Nmethylation of endocyclic or exocyclic amino groups, and the S-methylation of thiols. Arsenic methylation (not shown in this Figure) will also be discussed. An important aspect made explicit here is the fate of the positive charge carried by the sulfonium center. In most cases, the positive charge is lost in the form of a proton and the Nmethylated metabolite is more lipophilic than the parent compound. The exception is the N-methylation of pyridine-type N-atoms, which forms a quaternary ammonium group retaining the positive charge. This is pharmacokinetically relevant, since such positively charged metabolites are markedly more hydrophilic than the parent compound, resulting in accelerated excretion.
2180
Fig. 4.8. The main enzymes responsible for O-methylation are catechol O-methyltransferase (COMT) and phenol O-methyltransferase (PMT) [8]. The former is far more significant as far as xenobiotic metabolism is concerned, and little can be found about the latter in the relevant literature. COMT is mainly cytosolic (molecular weight of ca. 25 kDa) but also exists in membrane-bound form [13 16]. Both forms are products of a single gene, the membrane-bound form including an additional 50 residue segment at the N-terminus. The cytosolic form is expressed to high levels in the liver and kidneys, and the membrane-bound form predominates in the brain. The expression of COMT in human red blood cells has greatly facilitated its study. COMT fulfils important physiological functions by methylating (and inactivating) the catecholamine neurotransmitters dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine). As we shall see, it also methylates catecholestrogens. Its genetically reduced activity in ca. 25% of Caucasians may have therapeutic and physiopathological significance [13] [17].
2181
Fig. 4.9. O-Methylations are common reactions of compounds containing a catechol moiety, 4.3, with a usual regioselectivity for the meta-position (i.e., 4.4) over the paraposition (i.e., 4.5) [18]. The substrates can be xenobiotics and particularly drugs, as exemplified in the lower part of the Figure which summarizes a few results from an extensive investigation in which the rates of O-methylation of ca. 50 substrates were determined in the presence of recombinant human soluble COMT [18a]. In this Figure, selected substrates are arranged according to their rate of methylation by human recombinant soluble COMT. Very good substrates were for example 4-nitrocatechol (4.6) and caffeic acid (4.7). Fair substrates were catechol itself (4.8) and the drug dobutamine (4.9), a cardiostimulant b1-adrenoceptor agonist. The last row shows three well-known substrates whose rate of methylation was comparatively slow in vitro, namely the neurotransmitter dopamine (4.10), the anti-Parkinsonian drug l-DOPA (4.11), and (S)-carbidopa (4.12), a peripheral inhibitor of l-DOPA decarboxylase used in combination therapy to increase the efficacy of l-DOPA. Structure metabolism relationship studies showed that bulky substituents in adjacent positions decreased methylation, whereas increased acidity of a OH group favored it. A more refined analysis showed that increased ionization enhanced affinity for COMT, while the turnover rate and Vmax were favored by a high electron density on the phenolate Oatom, in other words, by a restricted delocalization of the negative charge. This is consistent with nucleophilicity of the target group favoring its methylation, in agreement with the electrophilic character of the CH3 group in S-adenosyl-lmethionine [18].
2182
Fig. 4.10. In addition to xenobiotic substrates, O-methylation can occur as a late event in the metabolism of phenolic or aryl groups, after they have been oxidized to catechols. This is exemplified here with two recently introduced drugs. Thus, traxoprodil (4.13) is a selective N-methyl-S-aspartate receptor antagonist of potential interest in neurodegenerative diseases and brain injury. One of the major metabolic pathways of the drug in humans is a CYP2D6-catalyzed oxidation to the catechol metabolite, followed by meta-O-methylation to 3-methoxytraxoprodil (4.14) [19]. Another informative example is that of duloxetine (4.15). This inhibitor of serotonin and noradrenaline reuptake contains a naphthalen-1-yl moiety which undergoes oxidation in humans at the 4-, 5- or 6-positions, followed by further oxidation [20]. A significant metabolite so produced is the catechol derivative 5,6-dihydroxyduloxetine (4.16), which was found to undergo O-methylation at either position with a predominance for the 6-OH group. The last example in this Figure is taken from phytochemistry, namely the tea polyphenol ()-epigallocatechin gallate (4.17). This compound shows two trihydroxyphenyl moieties, each of which is a potential target for COMT. Incubations with human or rodent soluble COMT revealed the fast methylation of the 4-OH group. This reaction was followed in a second step by the formation of the 4,4-dimethylated metabolite [21], the major metabolite of 4.17 detected in the urine of humans and rodents. Interestingly, these two metabolites were found to be strong noncompetitive inhibitors of COMT, possibly potentiating the activity of endogenous catecholamines [22].
2183
Fig. 4.11. Catechol O-methyltransferase is also of interest in the detoxification of catechol estrogens. Indeed, 17b-estradiol (4.18) is oxidized by cytochrome P450 to 2hydroxy- and 4-hydroxyestradiol (4.19 and 4.20, resp.). The catecholestrogens are oxidized by CYPs or peroxidases (PER) to the catecholestrogen quinones 4.21 and 4.22. These are reactive endogenous metabolites known to react with nucleic acids and to play a role in estrogen carcinogenesis [23]. In this context, it is important to note that COMT-catalyzed O-methylation is a protective pathway which decreases quinone formation by competing with oxidoreductases for the catechol substrates. The same pathways are known for estrone, the 17-keto analogue of 4.18. Of further interest in catecholestrogen O-methylation is the fact that 2-methoxyestradiol (4.23) attenuates cardiovascular and renal diseases. These effects were first detected after administration of 2-hydroxyestradiol (4.19). More recent in vivo studies in rats have revealed that the 2-O-methylation of 4.19 is so fast that this catecholestrogen is in fact a prodrug of 2methoxyestradiol (4.23) [24].
2184
Fig. 4.12. N-Methylation is a common pathway for several neurotransmitters and hormones. Besides these endogenous compounds, a significant number of exogenous amines are N-methylated. Several enzymes catalyze reactions of xenobiotic Nmethylation with different substrate specificities, e.g., nicotinamide N-methyltransferase (NNMT), histamine N-methyltransferase (HNMT), phenylethanolamine N-methyltransferase, and nonspecific amine N-methyltransferase [8] [12] [13]. This Figure presents an Enzyme Identity Card of NNMT and HNMT, both of which are cytosolic and are expressed in the liver and in a number of other organs. Histamine NMT has a narrow substrate specificity and plays a limited role in drug metabolism. However, a number of xenobiotic amines are known to inhibit it, e.g., ()-(S)-nicotine (see Fig. 4.15). This is a worrying cause of side-effects, all the more so since the enzyme is polymorphic in humans. Compared to HNMT, nicotinamide NMT is rather promiscuous and N-methylates a remarkable variety of xenobiotic aromatic azaheterocycles (see Fig. 4.15). As we shall see, the products are quaternary ammonium cations whose polarity and renal clearance are increased compared to the parent compound. In other words, nicotinamide NMT is a useful detoxification enzyme, but its marked interindividual variability also implies that detoxification of pyridine-type compounds is reduced in a fraction of the human population.
2185
Fig. 4.13. This Enzyme ID card features two other N-methyltransferases, namely phenylethanolamine N-methyltransferase (PNMT) and the nonspecific amine Nmethyltransferase (NMT) also known as indolethylamine N-methyltransferase (INMT) [8]. Phenylethanolamine NMT is a highly specialized enzyme which at best plays a very limited role in xenobiotic metabolism due to its restricted location (mainly the adrenal medulla) and narrow substrate specificity (noradrenaline and analogous phenylethanolamines) [13]. In contrast, amine NMT exists as two or more isozymes with broad and overlapping substrate specificities which include primary and secondary aromatic amines as well as aromatic azaheterocycles [25] [26]. Its role in xenobiotic metabolism is further increased by its wide distribution in organs and tissues, especially in the lung. However, much remains to be understood about this enzyme, and particularly the structural variety of substrates and inhibitors it recognizes.
2186
Fig. 4.14. Tetrahydroisoquinolines have been the objects of numerous investigations due to their potential toxification ultimately yielding neurotoxic ammonium cations showing a close analogy to methyl-4-phenylpyridinium (MPP ; see Fig. 2.94 in Part 2 [2]) [27]. This is well-illustrated by 1,2,3,4-tetrahydroisoquinoline (4.25) itself, an endogenous and exogenous cyclic secondary amine whose N-methylation (seemingly by amine NMT) yields the tertiary amine 4.26 [28a]. This metabolite is a precursor whose oxidation by monoamine oxidase yields the dopaminergic neurotoxic cation Nmethylisoquinolinium (4.27). Various endogenous and exogenous close analogues have been shown to undergo the same sequence of toxification [28b]. Carcinogenic aromatic primary amines such as 4-amino-1,1-biphenyl (4.28) and benzidine (4.31) are also substrates of amine NMT. Their first N-methylation is considered a reaction of toxification, since the secondary amine (e.g., 4.29) may then be oxidized by flavin monooxygenase to a hydroxylamine [2]. In contrast, the documented N-methylation of 4.29 to the tertiary amine 4.30 [25] is a detoxification, since N-oxygenation here yields a nontoxic N-oxide. Another toxicologically significant reaction of N-methylation is that of theophylline (4.32) to yield caffeine (4.33) [29]. This reaction goes countersense to the well-known oxidative N-demethylation reactions of methylxanthines [2], and it is not seen in adult humans. In contrast, it is effective in neonates (5 10% of a dose of theophylline) and may cause unwanted side-effects.
2187
Fig. 4.15. In this Figure, we exemplify the case of aromatic azaheterocycles, which, as mentioned above, can be N-methylated to yield a quaternary ammonium cation. Our first example is quite naturally nicotinamide (4.34), the physiological substrate of nicotinamide N-methyltransferase [12a]. This enzyme is the only one to utilize nicotinamide as a CH3 acceptor, but it also N-methylates other pyridine compounds. Indeed, amine NMT appears as the major but not only enzyme acting on pyridine (4.35; R H) and pyridine analogues, 4.35 (R = H) [26] [30]. The N-methylation of pyridine is clearly a reaction of detoxification, and indeed there exists a trend across animal species such that the more extensive its N-methylation, the lower its toxicity. A number of other azaheterocyclic compounds including quinoline (4.36), phthalazine (4.37), and quinoxaline (4.38) are also good substrates. A particularly interesting example is provided by nicotine [31] [32]. Whereas the unnatural ()-(R)-nicotine enantiomer (4.39) has been found to be a good substrate of amine N-methyltransferase from guinea pig lung to yield the quaternary ammonium compound 4.40, the natural ()-(S)nicotine (4.41) was a potent competitive inhibitor of (R)-nicotine N-methylation. The results in the cytosol of human liver cells again showed (R)-nicotine to be a good substrate, whereas here (S)-nicotine was a weak substrate.
2188
Fig. 4.16. S-Methyltransferases conjugate thiols into thiomethyl sulfides (Fig. 4.7), the two major enzymes in humans and animals being thiol methyltransferase (TMT) and thiopurine methyltransferase (TPMT). Whereas no direct comparison between the two enzymes seems to have been published, it is clear that thiol MT shows a much wider substrate specificity than thiopurine MT, and that markedly more medicinal substrates of the former are known. In other words, the clinical significance of thiol MT appears greater than that of thiopurine MT. Yet, despite these differences and the fact that both enzymes are polymorphic in humans, studies on the genetics and pharmacogenetics of TPMT still exceed those on TMT [13] [33]. In particular and at the time of this writing, no gene for TMT has been identified in humans. Besides these two enzymes, there exists also a thioether methyltransferase (EC 2.1.1.96; TEMT) which is briefly mentioned here. This enzyme methylated thioethers (i.e., RSR) to form sulfonium cations (i.e., RS (CH3 )R), and it also acts on ether-type selenium compounds. Few if any medicinal examples have been reported.
2189
Fig. 4.17. In Figs. 4.17 4.19, we survey a number of xenobiotic thiols whose Smethylation has been investigated. In agreement with the caption to Fig. 4.16, most of these compounds are substrates of thiol MT. A first and well-known example is that of captopril (4.42), the first marketed inhibitor of angiotensin-converting enzyme (ACE). This drug undergoes marked S-methylation in humans to the inactive metabolite 4.43, although this route is not the main one [34]. A high activity has been characterized in human hepatic and renal microsomes. The second example is a more recent one, omapatrilat (4.44), an inhibitor of both ACE and neutral endopeptidase (also known as a vasopeptidase inhibitor) and a potential new drug for the treatment of hypertension [35]. In humans and laboratory animals, this compound undergoes S-methylation to yield the first-generation metabolite 4.45, plus a number of later-generation Smethylated metabolites such as compound 4.46, methyl sulfoxides, and S-methyl-acyl glucuronides. As a whole, S-methylated metabolites accounted for a majority of a dose and demonstrated the significance of this pathway in the biotransformation of omapatrilat (4.44). It is interesting to note that these results do not appear to be isolated observations, since a comparable metabolic pattern was obtained with gemopatrilat, a closely related compound [36].
2190
Fig. 4.18. Further medicinal examples are shown here, beginning with a-lipoic acid (4.47), an endogenous cofactor as the (R)-enantiomer and an antioxidant drug as the racemate used in the treatment of diabetic polyneuropathy. When administered orally to humans, dogs, and rats, the drug was found to be extensively metabolized by boxidation (C2 chain shortening, see Chapt. 4.6) and reductive opening of the 1,2dithiolane ring (disulfide reduction) [37]. The latter reaction was followed by monoand di-S-methylation, yielding compounds 4.48, 4.49, and 4.50 as representative urinary metabolites in humans. The lower part of the Figure is dedicated to thiopurine MT substrates, most notably 6-mercaptopurine (4.52) and 6-thioguanine (4.54). These drugs have been used in the treatment of leukemia and autoimmune disorders, and in organ transplants [33]. Individual differences in response and toxicity have been correlated with polymorphism in the TPMT gene and with the resulting differences in the extent of thiol methylation to yield metabolites 4.53 and 4.55, respectively. Another relevant drug is azathioprine (4.51), which as a prodrug of 4.52 shows similar variability in response and toxicity.
2191
Fig. 4.19. Returning to thiol methyltransferase, we encounter prasugrel (4.56), a recent analogue of the well-known platelet anti-aggregant clopidogrel. Like the latter, 4.56 is a prodrug which must undergo a first activation step to a thiolactone (in this case metabolite 4.57) [38]. However, there is a significant difference between clopidogrel and prasugrel, whose thiolactone formation is catalyzed respectively by cytochrome P450 and carboxylesterases (cleavage of the acetate ester, followed by tautomerization and double-bond rearrangement). The actual activation is the second step, which leads to a reactive thiol metabolite, 4.58, the active species which irreversibly antagonizes platelet ADP receptors via a covalent SS bridge. In the case of prasugrel (4.56), this step to the reactive 4.58 is claimed to be catalyzed by CYPs; but given that the overall reaction from 4.57 to 4.58 is a hydrolytic one, all remains to be clarified regarding the postulated CYP-catalyzed mechanism. Given the reactivity and activity of the thiol metabolite 4.58, its own metabolism is of pharmacological significance, producing the S-methyl conjugate 4.59 and a cysteinyl disulfide conjugate (not shown). Our second example is that of metam (4.60), an agrochemical extensively used as a soil fumigant [39]. This is a toxic dithiocarbamate which is reversibly transformed in animals into the reactive methyl isothiocyanate (4.61) in a reaction involving glutathione (see Chapt. 4.7). The alternative, and irreversible, metabolic reaction is conjugation to Smethyl metam (4.62). This reaction appears as a detoxification although 4.60, 4.62, and other metabolites are inhibitors of mitochondrial aldehyde dehydrogenase.
2192
Figs. 4.20 and 4.21. Arsenic is present in many regions of the world where it diffuses from As-containing ores into water sources. It is thus a natural contaminant to which hundreds of millions of humans are exposed through drinking water. Arsenic is also an occupational hazard for workers and populations associated with smelting of copper and other metals. The contamination of the geosphere by arsenic causes severe health effects and cancer in exposed individuals. Thus, the inhalation of arsenic trioxide liberated by smelting causes lung cancer. The chemistry of arsenic is a rather complex one, since it exists in three valence states, namely metallic arsenic, trivalent arsenicals, and pentavalent arsenicals. Arsenic also exists as inorganic acids and salts, and as organoarsenicals produced in the biosphere, most notably methylarsenicals of relevance here, and thiol conjugates (Chapt. 4.7). The manifold toxicity of arsenic is due in particular to its capacity to inhibit numerous functional proteins by binding avidly to thiol groups. At the level of tissues and organs, arsenic is a carcinogen and may evoke severe inflammatory responses. For many years, the methylation of arsenic acids/ salts in organisms was considered to be a mechanism of detoxification. However, it is now known that methylated arsenicals contribute significantly to arsenic toxicity and genotoxicity [40]. Furthermore, some of the most toxic arsenicals are now believed to be methylated trivalent species [41]. A likely mechanism of DNA damage induced by methylated trivalent arsenicals involves the formation of reactive oxygen species, a fact that places arsenic redox reactions at the forefront of its toxicity [42]. Turning our attention to the metabolism of arsenic in humans and animals, Fig. 4.21 is so arranged that reactions of reduction appear horizontally, whereas reactions of methylation appear vertically. This Figure does not pretend to completeness, since no thiol-As metabolite or intermediate is shown [43], no more than dimethylarsine (Me2AsH), the product of reduction of dimethylarsinate (4.67). In humans chroni-
2193
cally exposed to arsenic, major methylated metabolites found in urine are 4.67 (cacodylate, dimethylarsinic acid) > dimethylarsinite (4.68; dimethylarsinous acid) > methylarsonate (4.65; monomethylarsonic acid) > methylarsonite (4.66; monomethylarsonous acid) [44]. Comparable results were obtained in human and rat hepatocytes [45]. The formation and excretion of trimethylated As species appears marginal, and there are only few reports on the excretion of trimethylarsine oxide (4.69) and trimethylarsine (4.70) in animals. An important finding is the fact that methylation occurs almost exclusively for trivalent arsenic species. Indeed, the major (exclusive?) enzyme in As methylation is specific for trivalent species and is, therefore, known as arsenic(III) methyltransferase (Fig. 4.20) [8] [46]. In concrete terms, pentavalent arsenicals must be reduced to trivalent arsenicals to allow their methylation [47 49]. Thus, arsenate (4.63) is reduced to arsenite (4.64). This step is catalyzed by at least two enzymes, glutaredoxin:arsenate oxidoreductase (EC 1.20.4.1) and arsenate:acceptor oxidoreductase (EC 1.20.99.1) [8]. The methylation of the trivalent arsenite (4.64) is catalyzed by AS3MT and yields the pentavalent methylarsonate (4.65). The latter is then reduced to methylarsonite (4.66) by glutathione:methylarsonate oxidoreductase (EC 1.20.4.2), an enzyme with absolute requirement for glutathione (GSH) and a member of the glutathione-S-transferases superfamily [48]. In turn, the trivalent methylarsonite (4.66) is methylated by AS3MT to the pentavalent dimethylarsinate (4.67), the major urinary metabolite of inorganic arsenic. The final steps to 4.68, 4.69, and 4.70 are minor ones whose enzymology is unclear.
Fig. 4.21.
2194
Fig. 4.22. This Chapter examines the formation of sulfates (ROSO ) and 3 sulfamates (RNRSO ) [5 8] [50]. Given the analogies between sulfates and 3 phosphates, the last Section of the Chapter will be dedicated to the (much rarer) reactions of xenobiotic phosphorylation. As shown here, the formation of sulfates and sulfamates consists in a sulfonate group ( SO ) being added to the substrate under 3 catalysis by a sulfotransferase. This group is carried by the cofactor 3-phosphoadenylyl sulfate (4.71; also known as 3-phosphoadenosine 5-phosphosulfate, PAPS). As the group is a sulfonate, the reactions of sulfoconjugation are correctly designated as sulfonations rather than the common term of sulfations [51]. All criteria of conjugation are met in sulfonation reactions, since they are enzymatic, and the group transferred is of medium molecular weight, ionized, and highly hydrophilic, and is carried by a coenzyme. In PAPS, the sulfuric and phosphoric moieties are linked by an anhydride bond whose cleavage is exothermic and supplies enthalpy to the catalytic reaction. Sulfonation reactions involve the nucleophilic attack on the S-atom by a OH group (in phenols, alcohols, hydroxylamines, and hydroxylamides), or a primary or secondary amino group. The by-product of the reaction is adenosine 3,5-bisphosphate (4.72; PAP). As we shall see, some sulfates are unstable under biological conditions and may undergo heterolytic cleavage to form electrophilic intermediates of considerable toxicological significance.
2195
Figs. 4.23 and 4.24. Sulfotransferases involved in the metabolism of small endogenous and exogenous molecules are soluble (cytosolic) enzymes. Following major advances in molecular biology, they are now recognized as being encoded by a gene superfamily of which ca. 50 mammalian genes are known, and whose products are classified into families ( > 45% residue identity) and subfamilies ( > 60% residue identity) according to their degree of homology [8] [10] [52 54]. Thus, human sulfotransferases include the SULT1A subfamily which contains the enzymes 1A1, 1A2, and 1A3 (phenol ( aryl) sulfotransferases, with some correspondence with EC 2.8.2.1); the subfamily SULT1B with the enzyme 1B1 (thyroid hormone sulfotransferase); the subfamily SULT1C with the enzymes 1C1 and 1C2; and the subfamily SULT1E with 1E1 (estrogen sulfotransferase, EC 2.8.2.4). All enzymes in the SULT1 family appear to have a marked preference for phenol substrates. In contrast, the SULT2 family has a distinct substrate specificity for alcohol substrates, and particularly hydroxysteroids. This family includes the subfamily SULT2A with 2A1 (alcohol/hydroxysteroid sulfotransferase, EC 2.8.2.14); the subfamily SULT2B with the two transcript variants 2B1a and 2B1b (EC 2.8.2.2); also included are steroid sulfotransferase (EC 2.8.2.15) and cortisol sulfotransferase (glucocorticosteroid sulfotransferase; EC 2.8.2.18). An important family is SULT3 with 3A1, which is involved in amine sulfonation and seems to correspond with amine sulfotransferase (EC 2.8.2.3). There is also a family SULT4 (with 4A1) whose substrate specificity is unknown, and which has been described as a brain sulfotransferase-like protein.
2196
It is important to note that there are marked and condition-dependent overlaps in the substrate specificity of all these sulfotransferases, a fact which prevents any strong and one-to-one correspondence between the classification of the Nomenclature Committee (NC) of the International Union of Biochemistry and Molecular Biology (IUBMB) [8], and the homology-based nomenclatures. Nevertheless, it is wellestablished that the enzymes of greatest significance in the sulfonation of xenobiotics are the aryl sulfotransferases, the alcohol sulfotransferases, and the amine sulfotransferases.
Fig. 4.24.
2197
Fig. 4.25. The upper part of this Figure shows a schematic and highly simplified depiction of the catalytic mechanism of sulfotransferases [55 57]. The numbering is that of estrogen sulfotransferase, and what the Figure shows is in fact the transition state. The weak bonds (ionic and H-bonds) are represented by red broken lines of exaggerated length for clearer vision. The sulfonate group in the center is still being weakly bound to the cofactor (PAPS in the process of becoming adenosine 3,5bisphosphate) and has begun binding to the substrate (here a generic phenol). At this stage, the transferred group is planar, with excess electronic density on the three peripheral O-atoms and an electron deficiency on the S-atom. Lys48 plays an important role in forming electrostatic bonds with the SO3 group and the phosphate moiety in PAP, thereby stabilizing the former. The nucleophilicity of the target O-atom in the substrate is increased by H-bond donation to His108. Other residues (among others Thr45 and Thr51) form H-bonds with the cofactor, the SO3 group, the substrate, or other important residues, thereby acting directly or indirectly to decrease the free energy level of the transition state and stabilize it. The lower part of the Figure states an important generalization about sulfonation reactions, which are of high affinity and low capacity. In concrete terms, they have a fast initial turnover rate, but their velocity decreases as the concentration of available cofactor is rapidly depleted [58]. The metaphor of a sprinter is a straightforward one, especially when contrasted with that of a marathon runner (i.e., the low-affinity, highcapacity reactions of glucuronidation, see Chapt. 4.4).
2198
Fig. 4.26. A more realistic view of the proximity between cofactor and substrate in the active site of sulfotransferase is presented. The structure of SULT1A1 crystallized with the cofactor and a phenolic substrate was retrieved from the Protein Data Bank (PDB ID: 2D06) [56]. A single monomer was used to build the image. The structure was completed by adding the H-atoms and minimized using VEGA; the image was generated by VMD and rendered by POVRay [59]. The optimized protein is colored using a color ramp, from blue (N-terminus) to red (C-terminus), and the ligands are depicted as Van der Waals space-filling models. The substrate is estradiol (4.18 in Fig. 4.11; the dark-grey model on the left of the picture), and the cofactor is a PAP analog (the violet model on the right; courtesy of Dr. Giulio Vistoli, University of Milan). Secondary structure elements are represented as coils for helices and arrows for b-strands. The Figure is also of general interest as it nicely illustrates the intricate manner by which the linear peptidic chain folds into a tertiary structure.
2199
Fig. 4.27. Beginning with model and xenobiotic phenols, we encounter two simple compounds used as probes of the major human hepatic sulfotransferase 1A1. For years, 4-nitrophenol (4.73) was used to this end, but recent results dispute its high selectivity, since it is also a substrate of 1B1 and other SULTs. In contrast, 2-aminophenol (4.74) has a high substrate affinity for SULT1A1 and is a poor substrate of other SULT1 enzymes [60]. A large number of other phenols were examined for their substrate behavior toward aryl sulfotransferases [61], yielding useful structure affinity relationships. Other phenols stand out for their environmental and toxicological significance, e.g., phenolic metabolites of polyhalogenated 1,1-biphenyls such as 2,5-dichloro-4hydroxy-1,1-biphenyl (4.75), 3,5,2-trichloro-4-hydroxy-1,1-biphenyl (4.76), and 3,5,2,4-tetrachloro-4-hydroxy-1,1-biphenyl (4.77). Phenols 4.76 and 4.77 were found to be substrates of human hydroxysteroid SULT2A1, making them potential competitors of the sulfonation of endogenous steroids. As for 4.75, it was identified as a non-substrate inhibitor of the enzyme [62]. These properties are a cause of concern as they suggest an interference with hormone regulation. Our last examples here are two xenobiotics of toxicological concern, namely bisphenol A (4.78; R H) and tetrabromobisphenol A (4.78; R Br). The latter is a flame retardant with demonstrated cytotoxicity, whereas the former is an endocrine disruptor and one of the highest volume chemicals produced worldwide, being used as a monomer and in many plastic consumer products such as toys and water containers [62]. Their conjugation may be hypothesized to be a route of detoxification, with formation of the mono-Oglucuronide (4.79; see Chapt. 4.4) clearly predominating over formation of the monoO-sulfate (4.80). Other examples of preferred glucuronidation over sulfonation will be presented later.
2200
Fig. 4.28. Many natural and endogenous compounds are substrates of sulfotransferases. Dopamine (4.10) is of particular interest, being both an essential neurotransmitter produced by decarboxylation of the amino acid l-DOPA (4.11; see also Fig. 4.9), and the active metabolite of the same l-DOPA used as a major anti-Parkinsonian drug. Dopamine of endogenous or exogenous origin is a good substrate of sulfotransferases and particularly SULT1A3 [63], with sulfonation being its major route of inactivation, and dopamine O-sulfate, 4.81 and 4.82, accounting for ca. 90% of all circulating dopamine in humans. The high selectivity of dopamine toward SULT1A3 is explained by the presence in the catalytic site of a carboxylate group forming an ionic bond with the ammonium group of dopamine and related amines; hence, its name of monoaminesulfating phenol transferase (see Fig. 4.23). The high regiospecificity of the enzyme for the meta-OH group (to yield 4.81) is also remarkable. For the sake of a broader vision, the Figure also shows two other routes of inactivation of dopamine, namely COMTcatalyzed O-methylation and MAO-catalyzed oxidative deamination. Numerous xenobiotics of plant origin are also substrates of sulfotransferases, in particular, dietary polyphenols [52] [64]. An example is provided here with (E)resveratrol (4.83), a polyphenol present in grapes and wine, and known to be endowed with cardioprotective activity. In vivo in rodents and in rat hepatocytes, the major metabolites were the 3-O-sulfate 4.84 and the 3-O-glucuronide [65]. In human hepatocytes, the major metabolites were the 3-O-glucuronide and the 4-O-glucuronide (see Fig. 4.42). In PAPS-fortified human liver cytosol (where no glucuronyltransferases are present, see Chapt. 4.4), three sulfates were produced, namely the 3-O-sulfate 4.84, 4-O-sulfate 4.85, and 3,4-O-disulfate. Incubations with recombinant enzymes uncovered the enzyme selectivities shown.
2201
Fig. 4.29. The previous Figure mentioned the role of monoamine-sulfating phenol transferase (SULT1A3) in the conjugation of xenobiotic analogues of dopamine. Here, we present three such analogues, namely b2-receptor agonists used in the treatment of asthma. As a rule, such drugs are quite hydrophilic and undergo substantial presystemic metabolism mainly by sulfonation. In vitro studies using human intestinal cytosol and recombinant human SULT1A3 have confirmed the effective sulfonation of several b2receptor agonists including isoprenaline (4.86; isoproterenol), terbutaline (4.87), and formoterol (4.88) [66]. While all drugs examined had comparable Vmax values, their affinity proved markedly structure-dependent, with isoprenaline being the best substrate. There was also a modest stereoselectivity such that the inactive ()-(S)enantiomers were somewhat better substrates. Besides drugs, a number of phenolic drug metabolites undergo sulfoconjugation, often in competition with glucuronidation (Chapt. 4.4). Traxoprodil (4.13; see also Fig. 4.10) offers a nice illustration of sulfonation occurring for both the drug and one of its metabolites [19]. As discussed in Chapt. 4.2, 4.13 undergoes CYP-catalyzed ring oxidation followed by COMTcatalyzed O-methylation to form 3-methoxytraxoprodil (4.14). Interestingly, both the drug and this metabolite form the respective sulfate esters 4.89 and 4.90 along with the O-glucuronides. Ring oxidation was the major route in most subjects, but direct conjugation by O-glucuronidation and O-sulfonation was the major metabolic pathway in poor metabolizers (i.e., persons with defective CYP2D6 activity; see Part 6).
2202
Fig. 4.30. The sulfonation of alcohols is also of metabolic significance, with the added feature that the resulting alkyl or cycloalkyl sulfate esters may be reactive. Like aryl sulfates, alkyl sulfates are sensitive to enzymatic and chemical hydrolysis; in addition, several alkyl sulfates are known to undergo proton-catalyzed heterolytic cleavage as discussed below. The enzymes involved in alcohol sulfonation are mainly alcohol/ hydroxysteroid sulfotransferases (see Fig. 4.23), but the involvement of other SULTs is sometimes documented. The influence of substrate structure on their sulfonation has led to some interesting generalizations [67]. Thus, the sulfonation of primary alcohols is distinctly faster than that of secondary alcohols, with that of tertiary alcohols being minute. This is well illustrated with three isomeric C7 alcohols, namely cyclohexylmethanol (4.91), trans-4-methylcyclohexanol (4.92), and 1-methylcyclohexanol (4.93). Another important rule is the fact that low-molecular-weight alcohols (less than six Catoms) are poor substrates. This is fortunate, given that sulfates of low-molecularweight alcohols such as methyl sulfate and ethyl sulfate are known alkylating agents. However, and as illustrated here and in the next Figure, some higher-molecular-weight sulfates may also be toxic. Thus, the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (4.94; NDPS) is a known nephrotoxin. Its oxidation and sulfonation in rats yielded the sulfate 4.95 which reacted very rapidly with glutathione (GSH; see Chapt. 4.7, hence the blue arrows) either directly or via the carbocation to form the conjugate 4.96 [68]. The latter is believed to be the ultimate nephrotoxin, since it is able to react with other endogenous nucleophiles in addition to GSH. Interestingly, the presence of the adjacent CH2 group allows intramolecular deactivation to the unsaturated maleimide analogue 4.97.
2203
Fig. 4.31. Reactive electrophiles are formed by the heterolytic COSO cleavage 3 (and NOSO cleavage, see next Figure) of sulfates [69]. This reaction is already 3 apparent in the previous Figure, and it is particularly worrying for genotoxic and carcinogenic polycyclic arylmethanols, as exemplified here [70 72]. CYP-Catalyzed hydroxylation of polycyclic methylarenes (here 5-methylchrysene (4.98)), followed by sulfonation catalyzed by hydroxysteroid sulfotransferases, produces the sulfate 4.99. This reactive conjugate can be detoxified by a direct substitution catalyzed by GSHtransferases (GST; Chapt. 4.7) to form 4.100; it also undergoes a heterolytic COSO 3 cleavage to generate the carbocation. Besides being inactivated by glutathione, the carbocation forms adducts with DNA, particularly at the nucleophilic NH2 group of adenine (see 4.101). The molecular features favoring heterolytic cleavage are partly known, the stability of the carbocation appearing as a significant determinant [69]. Resonance (i.e., delocalization of the positive charge) certainly contributes to the stabilization of the carbocation and hence to an increased likelihood of heterolytic cleavage. Such delocalization can be caused by an adjacent unsaturated system such as a carbonyl group (as in N-(3,5-dichlorophenyl)succinimide (4.94)), an aromatic system (e.g., methylarenes), or an allylbenzene structure (as in safrole, isosafrole, and analogues [69]).
2204
Fig. 4.32. A number of N-oxygenated compounds are also known substrates of sulfotransferases, for example, aryl sulfotransferase IV (EC 2.8.2.9) and SULT2B1 [70] [72] [73], thereby forming O-sulfates (also known as N,O-sulfates). Most known substrates in this broad class are hydroxylamines and hydroxylamides, as exemplified here with a simple and interesting model compound and industrial chemical, namely 2nitrotoluene (4.102) [74]. In male rats, three metabolites were found to be substrates of sulfotransferases, namely 2-nitrobenzyl alcohol (4.103), 2-aminobenzyl alcohol (4.104), and 2-(hydroxyamino)benzyl alcohol (4.107). The sulfonation of the latter two was concluded to account for covalent DNA binding in liver. The case of 4.104 is plainly similar to the examples discussed in Figs. 4.30 and 4.31, with the sulfate ester 4.105 forming a carbocation and the glutathione conjugate 4.106. The fate of 4.107 is of relevance here, since sulfonation of the NHOH group leads to a labile sulfate, 4.108, which undergoes proton-catalyzed heterolytic cleavage to a nitrenium cation stabilized by resonance as shown.
2205
Fig. 4.33. Hydroxylamides (also known as hydroxamic acids) might be even more carcinogenic than hydroxylamines following their toxification by sulfonation. Indeed, they are sulfonated faster than the corresponding hydroxylamines by aryl sulfotransferase IV (EC 2.8.2.9), and their sulfate esters are characterized by a great reactivity in aqueous media [75a]. Many conditions are, therefore, fulfilled for aromatic amines and their N-acetylated conjugates (see Chapt. 4.5) to form mutagenic, carcinogenic, and/or necrotic sulfate conjugates. A classical example is that of N-(9H-fluoren-2-yl)-Nhydroxyacetamide (4.109), a metabolite resulting from the CYP-catalyzed N-hydroxylation of N-(9H-fluoren-2-yl)acetamide, and a good substrate to rat liver aryl sulfotransferase IV and human liver SULT2B1 [75]. Its O-sulfate 4.110 reacts as shown to form a highly electrophilic nitrenium ion (whose detoxification is shown in Fig. 4.118). Despite the potential toxicity of sulfates of hydroxylamines and hydroxylamides, one should not conclude that O-sulfonation of N-oxygenated compounds always implies toxification. This is demonstrated with amidoximes such as benzamidoxime (4.112). This compound served as a model of amidoximes, some of which are of interest as bioreductive prodrugs (see Part 5) of medicinal amidines. The redox equilibrium between 4.112 and benzamidine (4.111) markedly favors reduction. Nevertheless, there were fears that the conjugation of amidoximes leading to the Osulfate 4.113 and the predominant O-glucuronide 4.114 (see Chapt. 4.4) might be a route of toxification. However, the two conjugates proved chemically stable and devoid of mutagenic effects [76]. An intriguing and rare reaction of conjugation occurs for minoxidil (4.115), a hypotensive agent also favoring hair growth. This drug is an Noxide, and the actual active form responsible for its therapeutic effects is its stable, zwitterionic N,O-sulfate 4.116 [77].
2206
Fig. 4.34. In contrast to unstable hydroxylamine sulfates, significantly more stable conjugates (i.e., sulfamates) are obtained upon N-sulfoconjugation of amines. One medicinally relevant example is that of trovafloxacin (4.117), a quinolone antibacterial agent. Human volunteers administered the drug excreted it partly unchanged and partly as three major conjugates, one of which was the sulfamate (4.118) which accounted for ca. 10% of the dose and was excreted fecally, indicating its stability against biodegradation by the gut microflora (see also Sect. 4.5.2) [78]. A number of alicyclic amines, and primary and secondary alkylamines, and arylamines can all yield sulfamates in the presence of human sulfotransferases, in particular SULT2A1 [79]. The involvement of amine sulfotransferase (EC 2.8.2.3) remains to be better understood, especially in humans. Examples of good substrates include the weakly basic (pKa 4 5) aromatic amines naphthalen-2-amine (4.119) and 1,2,3,4-tetrahydroquinoline (4.120). The basic (pKa 8 10) amines 1,2,3,4-tetrahydroisoquinoline (4.121) and octanamine (4.122) are also good substrates, but only when incubated at basic pH where they are in their neutral form. This may not necessarily be the rule for lipophilic medicinal amines such as desipramine, perhaps depending on the enzyme involved [80]. The sulfonation of a non-basic N-atom is also documented with luminol (4.123), a luminescent reagent used in forensic toxicology, and whose fate was investigated in rats to search for possible toxic metabolites [81]. Besides the parent compound ( < 5% of a dose), only two inert metabolites were found, namely the sulfamate 4.124 (ca. 30%) and the N-glucuronide 4.125 (ca. 60%; Chapt. 4.4).
2207
Fig. 4.35. Phosphate conjugates are rare compared to sulfates but are of primary significance in the metabolism of anticancer and antiviral agents impacting on endogenous nucleotides. Indeed, phosphorylation is an essential metabolic step in the bioactivation of these agents, and numerous studies document their stepwise phosphorylation to mono-, di-, and triphosphates. Such reactions are sometimes, and correctly, labeled as anabolic (i.e., biosynthetic) ones [82]. They are known or postulated to be catalyzed by some among the many phosphotransferases (EC 2.7), for example, adenosine kinase (EC 2.7.1.20), thymidine kinase (2.7.1.21), pyruvate kinase (2.7.1.40), uridine kinase (2.7.1.48), deoxycytidine kinase (EC 2.7.1.74), deoxyadenosine kinase (EC 2.7.1.76), nucleoside phosphotransferase (EC 2.7.1.77), creatine kinase (EC 2.7.3.2), adenylate kinase (EC 2.7.4.3), nucleoside-phosphate kinase (EC 2.7.4.4), nucleosidediphosphate kinase (2.7.4.6), guanylate kinase (EC 2.7.4.8), (deoxy)nucleoside-phosphate kinase (EC 2.7.4.13), and pyrimidine nucleoside monophosphate kinase (2.7.4.14) [8]. An example is afforded by the well-known anti-HIV agent zidovudine (4.126; AZT, azidodeoxythymidine). The concentrations of its phosphate anabolites were measured in the peripheral blood mononuclear cells of AIDS patients treated with the drug [83]. The monophosphate 4.127 was the predominant compound; the diphosphate 4.128 and triphosphate 4.129 were present in minor and comparable amounts. The unexpected activity of phosphotransferases toward xenobiotic substrates is also seen with FTY720 (4.130), a novel immunomodulator used in transplantations and to treat autoimmune diseases [84]. The agent is phosphorylated in rats and humans to the active monophosphate 4.131. The reaction is catalyzed by sphingosine kinases and is highly productenantioselective. Indeed, FTY720 (4.130) itself is prochiral (it bears two enantiotopic CH2OH groups), and its enzymatic phosphorylation yields exclusively the enantiomer of (S)-configuration (see 4.131), which is also the only active one.
2208
Fig. 4.36. Together with glutathione transferases (Chapt. 4.7), glucuronosyltransferases count as the most significant conjugating enzymes in xenobiotic metabolism. This is explained in qualitative terms by the diversity of functional groups to which glucuronic acid can be coupled, and quantitatively for the vast number and diversity of their substrates [5 10] [50] [85]. Here, we begin with the biochemistry of glucuronidation, leaving the presentation of the enzymes proper (UGTs) for later Figures. Glucuronidation consists in a molecule of glucuronic acid being transferred from the cofactor uridine-5-diphospho-a-d-glucuronic acid (4.132; UDPGA) to the substrate. This cofactor is produced endogenously by the C(6) oxidation of UDP-a-d-glucose, and it is recognized that ca. 5 g are synthesized daily in the adult human body, hence the high capacity of this metabolic route. Glucuronosyltransferases are low-affinity enzymes compared to sulfotransferases, which implies that sulfonation is usually faster than glucuronidation at low substrate doses or concentrations (see Fig. 4.25). Glucuronic acid in UDPGA (4.132) exists in the (1a)-configuration, but the products of conjugation are b-glucuronides 4.133. This is due to the mechanism of the reaction being a nucleophilic substitution with inversion of configuration. Indeed, all target sites in substrates are nucleophiles, a common characteristic they share despite their great chemical variety. An important feature of glucuronides is their acidity. The pKa of glucuronic acid is 3.0, and that of O-glucuronides in the range 2.9 3.1, implying nearcomplete ionization in the physiological pH range [86].
2209
Fig. 4.37. The previous Figure contains a summary of the functional groups being potential substrates for UDP-glucuronyltransferases. This overview is presented here in greater detail and shows the electron-rich target sites of glucuronidation. First, there are the OH groups in phenols, alcohols, hydroxylamines, and hydroxylamides, which form O-glucuronides. An important class of O-glucuronides are also the acyl glucuronides formed from carboxylic acids (shown here) and carbamic acids (RRNCOOH; see Chapt. 4.8). The N-glucuronides are generated from primary and secondary aliphatic or aromatic amines, saturated secondary heterocyclic amines, amides and sulfonamides (all of which are represented as RRNH in the Figure). Another group of N-glucuronides are formed from tertiary amines, be they aliphatic, saturated heterocyclic, or aromatic (i.e., of the pyridine type). These N-glucuronides are special in the sense that they contain a permanent positive charge in addition to the negative charge of the carboxylate; they are thus zwitterions [87]. Thiols and thioacids can lead to S-glucuronides. A few strongly acidic enolic acids are known to form Cglucuronides. In summary, the products of glucuronidation are grouped into four main classes, namely O-, N-, S-, and C-glucuronides, depending on the site of attachment of the C(1)-atom in glucuronic acid.
2210
Figs. 4.38 4.40. The enzymes catalyzing the highly diverse reactions of glucuronidation are known as UDP-glucuronosyltransferases (UDP-glucuronyltransferases; UGTs) and consist in a number of proteins coded by genes of the UGT superfamily [6 8] [88 94]. These enzymes are part of the glycosyltransferases, and we shall see in Sect. 4.4.9 that UGTs are also able to catalyze conjugations with glucose and a few other hexoses [95]. The human UGTs known to metabolize xenobiotics are the products of (to date) four gene families (UGT1, UGT2, UGT3, and UGT8). These are membranebound enzymes found in the endoplasmic reticulum. Their tissular distribution is quite broad, with noteworthy organs being the liver and bile ducts, kidneys, gastrointestinal tract (esophagus, stomach, small intestine, and colon), reproductive organs (the mammary glands, testes, and prostate), and the skin. Endogenous substrates include a variety of androgens (testosterone, androsterone, epiandrosterone), estrogens (bestradiol, estriol) and gestagens (17a-hydroxyprogesterone), biliary acids (lithocholic acid, deoxycholic acid, chenodeoxycholic acid), and bilirubin (a waste product of hemoglobin) whose detoxification by UGTs is of major significance in humans [92]. A number of polymorphisms have been reported in the UGT1 and -2 families. Thus, mutations in 1A1 cause hereditary unconjugated hyperbilirubinemia (i.e., Crigler Najar and Gilbert syndromes). Other polymorphisms are known in, e.g., UGT1A3 to 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17. A list of human UGTs is shown in Fig. 4.39 together with the major classes of their substrates [96] [97]. This is complemented in Fig. 4.40 with the evolutionary relationship of human UGTs in families 1 and 2 [88] [89].
2211
Fig. 4.39.
Fig. 4.40.
2212
Fig. 4.41. The Figure shows the ribbon structure of UGT2B7 complexed with UDPglucuronic acid and morphine. The ribbon is colored using a ramp of color from blue for N-terminus to red for C-terminus. The ligands are represented as Van der Waals spheres (green for morphine and cyan for the cofactor UDPGA). The structure of the enzyme was generated combining the C-terminal domain (Ala285 Ser446) whose structure was experimentally resolved (PDB 2O6L [98]) with the model of N-terminus (Gly24 Pro284, the putative signal peptide from Met1 to Cys23 was discarded) which was generated by homology techniques. In detail, the N-terminal domain was modeled by Fugue exploiting its homology with the macrolide glycosyltransferase from Streptomyces antibioticus (PDB 2IYF). The predicted backbone was completed by adding the side chains and the H-atoms using VEGA and was joined to the experimental C-terminus by superimposing the common residues. With the apoprotein structure minimized, the tertiary complex was generated by docking first UDPGA, followed by morphine. Specifically, the ligands were docked manually optimizing their known interactions with pivotal residues of the UGT2B7. The resulting structure was finally minimized to optimize the relative position of the bound ligands (courtesy of Dr. Giulio Vistoli, University of Milan; see also Fig. 4.26).
2213
Fig. 4.42. Our overview of UGTs substrates begins with phenols, and quite logically with plant phenols. Indeed, herbivores and omnivores have been exposed to such nonnutritious compounds throughout their evolutionary history, which explains the evolution of detoxifying enzymes to facilitate their elimination, SULTs and UGTs among them [99]. Thus, (E)-resveratrol (4.83) is found in a variety of plant sources, most notably grapes, and is known for its antioxidant, lipid-lowering, cardioprotective and chemopreventive activities. Both sulfonation (see Fig. 4.28) and glucuronidation are significant reactions in humans, their relative importance depending on dose (i.e., low doses allow for higher degrees of sulfonation, see Fig. 4.36). The two Oglucuronides of (E)-resveratrol (4.83) are shown here together with the human UGTs that catalyze their formation. Human liver microsomes produced more 3-O-glucuronide, 4.135, than 4-O-glucuronide, 4.136, a product regioselectivity reversed in human intestine microsomes. Overall, the latter were markedly more active than the former [100]. Two further examples of product regioselective glucuronidation are seen with bioflavonoids such as baicalin and quercetin. Baicalin (4.137) bears OH groups on its B-ring only; in the presence of human or rat liver or intestinal microsomes, the rates of O-glucuronidation were higher at 7-OH than at 6-OH, with no reaction detected at the 5-OH group. 7-O-Glucuronidation was catalyzed by the human enzymes 1A9 > 1A8 > 1A3 > 2B15 > 1A7. UGT1A1 was the most efficient, but only at very low substrate concentrations [101]. Quercetin (4.138) is more complex as it contains four phenolic and one phenol-like OH group. Its regioselective glucuronidation is also markedly dependent on enzyme and tissue, with the 3- and 3-positions seemingly emerging as preferred over the 7- and 4-positions [102].
2214
Fig. 4.43. An apt transition between natural products and medicinal compounds is provided by morphine (4.139). This major medicine contains a phenol function (the 3OH group) and a secondary alcohol function (the 6-OH group). Both groups are glucuroconjugated, yielding morphine 3-O-glucuronide (4.140) and morphine 6-Oglucuronide (4.141), respectively. In most laboratory species and in humans, the former is produced in higher amounts than the latter. In humans, these reactions are catalyzed mainly by UGT2B7. Lower amounts of two other conjugates have also been found in a number of species, namely the 3,6-O-diglucuronide and morphine 3-O-sulfate (not shown here) [103]. Of great clinical significance is the fact that morphine 6-Oglucuronide is a highly active agonist at the opiate m-receptor, and that both the 3-Oand the 6-O-glucuronides accumulate in the serum of renally impaired patients chronically treated with morphine. The presence of UGT2B7 in human central nervous system provides further evidence for the therapeutic contribution of its 6-Oglucuronide to the analgesic activity of morphine. Another important example is that of paracetamol (4.142), a nonprescription drug widely used for its mild analgesic and antipyretic properties. At therapeutic doses, its main metabolite is the O-glucuronide 4.143 (ca. 50 60% of total urinary metabolites). A number of UGTs can glucuronidate paracetamol, the most active ones being UGT1A1, 1A6, and 1A9. A further but somewhat less important conjugate is the O-sulfate 4.144 (ca. 30 40% of total urinary metabolites). CYP-Catalyzed oxidation (a route of toxification) represents less than 5% of a dose [104] (see also Parts 2 and 3). At hepatotoxic doses, the sulfonation capacity is exceeded and glucuronidation predominates (2/3 to 3/4 of metabolites), with oxidation also increasing (7 15%).
2215
Fig. 4.44. Another medicinal example of glucuronidation is ezetimibe (4.145), an inhibitor of the intestinal absorption of exogenous cholesterol used in the treatment of primary hypercholesterolemia, alone or in combination with cholesterol-lowering drugs acting by another mechanism (e.g., statins). Ezetimibe (4.145) is interesting as a substrate of UGTs in that it contains two target sites, namely a phenol and an alcohol group. The phenolic glucuronide 4.146 (formed by UGT1A1, 1A3, and 2B15) is produced in much larger proportions than the benzylic metabolite 4.147 (formed by UGT2B7) [105]. In fact, the phenolic metabolite is the main circulating metabolite in human plasma; it is also and by far the major in vitro conjugate in human liver microsomes. In contrast, human jejunum microsomes produced the two O-glucuronides in similar amounts. Both conjugates are excreted mainly in bile and undergo enterohepatic cycling. This phenomenon is clinically relevant, given that the pharmacological target of 4.145 is an intestinal cholesterol transporter, and that its glucuronides are also active. A number of other drugs have their therapeutic effects prolonged by enterohepatic cycling, as nicely illustrated in a pharmacokinetic study of estradiol in postmenopausal women administered a single oral dose of 1.5 mg [106]. In this Figure, we simply show the structure of estradiol (4.18) in redox equilibrium with its metabolite estrone (4.148).
2216
Fig. 4.45. This Figure continues and complements the previous one by illustrating some of the pharmacokinetic results obtained in the clinical study under discussion [106]. Both estradiol (4.18) and its metabolite estrone (4.148) were extensively Oglucuronidated and underwent enterohepatic cycling. An experimental proof of this phenomenon can be seen in the time profile of the serum concentrations of both hormones. The time profile of estradiol shows a first phase of absorption elimination with an approximate half-life of 2 h. However, a second absorption phase rapidly kicked in and resulted in sustained levels of estradiol for 24 h and more. The serum concentration curve of the metabolically produced estrone showed enterohepatic absorption phases after ca. 24 and 50 h, extending its half-life from 4 h after the first absorption phase to 11 h. Estrone levels were markedly higher than estradiol levels (cmax % 130 vs. 30 ng/l). It is known from numerous literature data that large hydrophilic anions are actively secreted in the bile ducts as substrates of organic anion transporters whose primary substrates are biliary acids produced in the liver. By virtue of their negative charge, the glucuronides of sufficiently large aglycones fulfill the physicochemical conditions for biliary excretion. As a rule of thumb, the biliary excretion occurs above a threshold of ca. 450 500 Da in humans and 350 400 Da in rats. However, biliary excretion is a necessary but not sufficient condition for enterohepatic cycling, since the glucuronide must also be hydrolyzable by bacterial and/or intestinal glucuronidases [6] [107] [108]. And the aglycone liberated by hydrolysis must obviously be absorbable by the intestinal wall.
2217
Fig. 4.46. Alcohols can be glucuronidated with relative ease, producing O-glucuronides whose chemical stability contrasts with the reactivity of O-sulfates (see Sect. 4.3.3). To follow the same sequence as Chapt. 4.3, we devote a Figure to natural alcohols, beginning with steroidal hormones [109]. These endogenous compounds and their synthetic analogues are well known substrates of UGTs in humans and animals. Interestingly, recent studies using powerful new technologies have identified a novel class of glucuronides resulting from the sequential glucuronidation of a single OH group. This is illustrated here with 5a-dihydrotestosterone (4.149), the active metabolite of testosterone. Its glucuronidation at the 17b-OH group to yield the monoglucuronide 4.150 was catalyzed by human UGT2B17, 2B15, 1A8, and 1A4 in decreasing order. Incubation of the monoglucuronide resulted in a low but measurable production of the diglucuronide 4.151 having the two glucuronyl moieties linked at the 1 ! 2 position. This reaction was catalyzed by UGT1A8 and, to a lesser extent, by 1A1 and 1A9. However, UGT1A8 was the only human UGT capable of producing the diglucuronide from 5a-dihydrotestosterone. Alcohols of plant origin are numerous and, like natural phenols, have been consumed by herbivores for hundreds of millions of years, explaining for a good part the evolution of the UGT gene superfamily. As examples, ( )-borneol and ( )-linalool are two terpenoid alcohols known to form the respective glucuronides 4.152 and 4.153 [110]. Note that borneol is a secondary alcohol, whereas linalool is a tertiary one, a point we shall take up in the next Figure.
2218
Fig. 4.47. This Figure addresses the issue of chemoselectivity and regioselectivity in reactions of glucuronidation (see also Part 1 [1] [4]). Chemoselectivity implies the discrimination between chemically diverse target groups, here between primary, secondary and tertiary alcoholic groups, independently of their presence in the same or different compounds. When chemically diverse alcohol groups are present in the same molecule, chemoselectivity overlaps partly with regioselectivity, as seen with the antibiotic chloramphenicol (4.154). Human microsomes produced both the 3-Oglucuronide (at the primary OH group) and the 1-O-glucuronide (at the secondary OH group), with a ca. tenfold preference for the former [111]. However, such a result cannot be generalized given its dependence on species and isozymes. Thus, the antithrombotic agent AZ11939714 (4.155) was glucuronidated at the secondary OH group at C(2) in dog microsomes, at the primary 4-CH2OH group in human microsomes, and mainly at the secondary OH group at C(3) (with some glucuronidation at the 4-CH2OH group) in rat microsomes [112a]. The results in humans are consistent with the high O-glucuronidation of AZT (4.126; Fig. 4.35) at its corresponding CH2OH position, a reaction catalyzed by human UGT2B7 [112b]. The lower part of the Figure shows relevant metabolites of 1,1-dimethylpropyl methyl ether (4.156) in rats [113], which affords a further example of the glucuronidation of a tertiary alcohol. Indeed, CYP-catalyzed oxidation of 4.156 led to 1,1-dimethylpropan-1-ol (4.157), a minor urinary metabolite. Major urinary metabolites were 2-methylbutane-2,3-diol (4.158) resulting from further oxidation, the glucuronide (4.159) of the tertiary alcohol 4.157, and the 3-O-glucuronide 4.160 of 2-methylbutane-2,3-diol (4.158; i.e., at its secondary alcoholic group). Comparable urinary ratios were seen in a single human volunteer, except for 4.157 which was a major metabolite, and the glucuronide 4.160 which was a minor.
2219
Fig. 4.48. Another type of selectivity is seen in some glucuronidation reactions as well as in various other phase I and phase II metabolic reactions, namely the preference of some UGTs for one enantiomer over the other, and more generally for one stereoisomer over the other(s). Because we prefer to use the term selectivity for reactions and specificity for enzymes [1] [4], what is presented here are examples of the enantiospecificity of UGTs. The b-blocker propranolol (4.161) is a chiral drug existing as two stable forms, the active (S)-enantiomer (i.e., the eutomer) and the inactive (R)-enantiomer (i.e., the distomer). Because d-glucuronic acid is itself a chiral, enantiomerically pure compound, the glucuronidation of propranolol (4.161) yields two diastereoisomeric glucuronides. In humans administered racemic propranolol, plasma and urinary levels of (S)-propranolol glucuronide are higher than those of (R)-propranolol glucuronide. In other words, the overall reaction of propranolol glucuronidation is substrate-enantioselective. The origin of this selectivity has now been ascribed (at least in part) to three UGTs, namely UGT1A9 and 1A10, which show a marked enantiospecificity for (S)- and (R)-propranolol, respectively, and UGT2B7, whose preference for (R)-propranolol is minute [114]. The case of oxazepam (4.162) is both similar to and different from that of propranolol. The stereogenic center in this compound is a highly unstable one, such that the drug racemizes with an estimated halflife of 1 4 min under physiological conditions of pH and temperature [115]. Yet, UGTs acting on this substrate do show enantiospecificity, since UGT1A9 and 2B7 glucuronidate (R)-oxazepam, whereas UGT2B15 is specific for (S)-oxazepam [116].
2220
Fig. 4.49. Hydroxylamines and hydroxylamides may also form O-glucuronides. Thus, a few drugs and a number of aromatic amines are known to be N-hydroxylated and then O-glucuronidated. An example is found in the metabolism of the candidate hypoglycemic agent 9-[(1S,2R)-2-fluoro-1-methylpropyl]-2-methoxy-6-(piperazin-1yl)purine (4.163) [117]. When administered to monkeys, more than half of a dose was recovered as a compound found to be the O-glucuronide, 4.165, of the Nhydroxylated metabolite 4.164. The possibility of the metabolite being an Nglucuronide was conclusively excluded. It is also interesting to note that all results reported in this study are consistent with a good chemical stability of the O-glucuronide 4.165, in contrast to some O-sulfates of hydroxylamines and hydroxylamides as discussed in Sect. 4.3.4. Zileuton (4.166), an inhibitor of 5-lipoxygenase, has value in the treatment of asthma and other inflammatory pathologies. It is an unusual drug in that it contains a hydroxylamido group which proved to be a major target of human UGT [118]. Indeed, ca. 75% of a dose are recovered as the O-glucuronide 4.167 in human urine. Interestingly, human and monkey liver microsomes catalyze the formation of this metabolite, but rat liver microsomes do not. Substrate enantioselectivity is also documented, since the glucuronidation rate of (S)-zileuton in human liver microsomes is ca. four times higher than that of its (R)-enantiomer, explaining the faster clearance of the (S)-isomer in humans.
2221
Figs. 4.50 4.52. An important reaction catalyzed by UGTs is the formation of acyl glucuronides, 4.168, whose significance is now recognized due to their potential toxification [119]. These metabolites are quite reactive due to the combination of an ester and an acetal function. Intermolecular reactions with nucleophilic compounds include hydrolysis [107] [108], transacylation with glutathione (Chapt. 4.7) [120], and direct transacylation of proteins [121], leading to potentially immunogenic and antigenic proteins. These reactions are in competition with intramolecular nucleophilic rearrangements, particularly internal migration of the acyl moiety to the 2-O, 3-O, and 4-O positions [122]. In the resulting positional isomers 4.169, 4.171, and 4.173, respectively, the 1-hydroxy hemiacetal is free and able to undergo the well-known reversible ring opening of reducing sugars, yielding the acyclic isomers 4.170, 4.172, and 4.174, respectively. These are reactive hydroxy aldehydes which can bind covalently to nucleophilic groups in biomacromolecules, particularly to NH2 groups in blood and tissue protein. The resulting imine 4.175 (a Schiff base) isomerizes to a more stable form known as an Amadori compound, 4.176 [123] [124]. Covalent binding of reducing sugars to proteins (i.e., glycation) is a phenomenon of toxicological concern. Indeed, the protein adducts (and to a minor extent the acyl glucuronides in their acyclic form 4.172) can undergo autoxidation catalyzed by transition metal ions. The enaminol 4.177 and enediol 4.179 tautomers appear to be intermediates, while the products of autoxidation are reactive oxygen species (ROSs), reactive carbonyl species (RCSs; e.g., 4.178 and 4.180), and advanced glycation endproducts (AGEs) [125]. These processes of glycation and autoxidation are known as glycoxidation and may in some cases lead to a variety of pathologies [126] in a few sensitive individuals, and in case of abuse of acyl glucuronide-forming drugs.
2222
Fig. 4.51.
Fig. 4.52.
2223
Fig. 4.53. A specific reaction of intramolecular nucleophilic elimination is shown by a number of statins, i.e., cholesterol-lowering drugs that act by inhibition of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase. Two of the marketed statins are used in the lactone, prodrug form, namely lovastatin and simvastatin (4.181), while most others are used as the active hydroxy acids (e.g., atorvastatin, fluvastatin, and pravastatin) [107]. The metabolism of statins is a complex one. There is a nonenzymatic lactone/hydroxy acid equilibrium which is comparatively fast under gastric conditions of acidity (t1/2 of ca. 1 h with an equilibrium constant close to one) but much slower at neutral pH [127]. Enzymatic lactone-ring opening can also occur, in particular, by serum paraoxonase [3] [4]. The COO group in the hydroxy acid form of statins is an active target of phase-II metabolism involving conjugates as intermediates and/or metabolites. Of relevance here is the fact that glucuronidation of the COO group leads to an acyl glucuronide, 4.183, which was detected in the in vitro metabolism of simvastatin acid (4.182; and atorvastatin, among others). These acyl glucuronides were characterized both as metabolites and as intermediates, since they spontaneously undergo cyclization elimination to form the d-lactone [128]. Other examples of acyl glucuronides undergoing cyclization elimination begin to be reported [129].
2224
Fig. 4.54. Figs. 4.50 4.52 might leave the reader with the conclusion that acyl glucuronides are consistently dangerous metabolites. Fortunately, this is not the case, and numerous drugs metabolized to acyl glucuronides have been cleared for safety, with the usual proviso that dosage guidelines must be respected and exaggerated use avoided. In addition, a minute proportion of patients may be sensitive to the immunogenic and antigenic potential of proteins adducts [130]. The endogenous UGT substrate bilirubin (4.184) is of high interest in this context. This breakdown product of hemoglobin is markedly toxic beyond the physiological threshold, causing jaundice and neurological disorders. Its route of detoxification and elimination is via glucuroconjugation, followed by biliary excretion. Bilirubin contains two COOH groups, and indeed the three possible acyl glucuronides (namely the two monoglucuronide isomers 4.185 and 4.186, and the diglucuronide 4.187) have been found in rat bile [131]. Their incubation with human serum albumin under physiological conditions of pH and temperature resulted in a marked formation of acyl glucuronide albumin adducts. Covalent binding occurred by the Schiff-base mechanism, predominantly to the free amino group of Lys190. We note here that the formation of albumin adducts does not prevent bilirubin glucuronidation from being a reaction of detoxification which evolved to protect animals from the intrinsic toxicity of this breakdown product.
2225
Fig. 4.55. Our overview of acyl substrates of UGTs continues with benzoic acids [132]. A significant finding connected with potential toxicity of acyl glucuronides is a linear relationship between their rate of degradation (hydrolysis plus acyl migration) and their propensity to bind covalently to serum albumin [123c]. Thus, the diuretic furosemide (4.188) forms a comparatively stable glucuronide and few adducts. In contrast, the uricosuric agent probenecid (4.189) forms a labile glucuronide and is markedly reactive toward plasma proteins [133]. In contrast, the nonsteroidal antiinflammatory drug (NSAID) mefenamic acid (4.190) forms a comparatively stable acyl glucuronide [121a] [134]. Electronic and steric factors are postulated to determine the relative reactivities of these glucuronides. The NSAID diflunisal (4.191) is interesting due to the presence of two target sites for UGTs. While the phenolic glucuronide is stable and readily excreted, the acyl glucuronide is reactive and undergoes in part hydrolysis or isomerization, followed by covalent binding. In rats dosed with the drug, protein adducts were found in the serum as well as in tissues such as the liver, kidneys, and lungs [124a] [135]. Our last two examples illustrate the fact that many UGTs are able to form acyl glucuronides. In the case of salicylic acid (4.192), twelve human expressed UGTs were examined (eight in subfamily 1A and four in subfamily 2B), all of which, except 1A4, 2B15, and 2B17, were found to be active toward this substrate [136]. The ratio of phenolic over acyl glucuronide formed varied markedly among these enzymes. As for the anti-allergic drug tranilast (4.193), its main metabolic pathways in humans are O-demethylation and glucuronidation [137]. The latter reaction is catalyzed mainly by UGT1A1, leading in some individuals to hyperbilirubinemia due to competition with bilirubin (4.184) glucuronidation.
2226
Fig. 4.56. The medicinal UGT substrates presented here were selected for the additional information they offer. Zomepirac (4.194) and tolmetin (4.195) are two arylacetate NSAIDs known for their relatively high reactivity and covalent binding to proteins [122] [123c]. Looking at chiral drugs [138], (S)-etodolac (4.196) is the active enantiomer of etodolac. This drug is extensively conjugated in humans to a rather reactive acyl glucuronide, the reaction in human liver microsomes being ca. fourfold faster for the active (S)-etodolac than for its enantiomer [139]. Human UGT1A9 was the major enzyme involved in (S)-etodolac glucuronidation, with low contributions from 1A10 and 2B7. With the exception of 2B7, individual UGTs showed very low activity toward (R)-etodolac. Ketoprofen is a NSAID representative of the chiral 2arylpropanoates known as profens. In contrast to the previous examples, its acyl glucuronide is of relatively low reactivity. Interestingly, the overall rate of degradation and the 1b- to 2b-acyl migration of the glucuronide of (R)-ketoprofen (4.197) were twofold faster than those of its epimer formed from (S)-ketoprofen [122] [138]. Naproxen (used as the (S)-enantiomer 4.198) is another member of the profen family. Its glucuronidation by rat UGT1A1 was markedly enantioselective for the (R)-form, whereas no substrate enantioselectivity was seen with the human 1A1 orthologue [140a]. At pH 7.4 and 378, naproxen glucuronide hydrolyzed and isomerized at similar rates [121] [140]. Also, covalent binding occurred by both transacylation and glycation. Our last examples are the anti-HIV candidate 3-O-(3,3-dimethylsuccinyl)betulinic acid (4.199) [141] and hypolipidemic agent gemfibrozil (4.200) [124b], both of which contain hindered COOH groups. While 4.199 formed relatively stable acyl glucuronides, gemfibrozil-glucuronide was rather unstable and reactive. This illustrates the difficulty of making qualitative reactivity previsions based on chemical structure.
2227
Fig. 4.57. Second in importance after O-glucuronidations are the N-glucuronidations, due to the variety of target groups and substrates. One characteristic of many Nglucuronides compared to O-glucuronides is their greater chemical and enzymatic stability, excepting their easier hydrolysis in the acidic pH range. Also noteworthy are the species differences in the glucuronidation of tertiary amines to form quaternary Nglucuronides [142]. Among carboxamides and sulfonamides, an important example is the antiepileptic drug carbamazepine (4.201) whose primary carboxamido group is conjugated to form the N-glucuronide 4.202 [143]. The reaction is catalyzed by UGT2B7 in microsomes from human liver, kidney, and intestine. Lactam glucuronidation is illustrated with MaxiPost (4.203; GMS-204352), a potent and specific maxi-K channel opener [144]. Its major metabolism in humans was the N-glucuronide, which proved stable in buffers and in the presence of glucuronidases; only 2B7 catalyzed its formation. Examples of primary and secondary sulfonamides are provided by valdecoxib and sulfonamides, respectively. Valdecoxib (4.204) was extensively metabolized in humans by oxidation and further conjugations. In addition, a major metabolite was its N-glucuronide resulting from direct glucuronidation at the sulfonamido group [145]. The case of antibacterial sulfonamides is of toxicological significance. The metabolism of these drugs occurs mainly by conjugation and involves a competition between N-acetylation of the primary N(4)H2 group (see Chapt. 4.5) and N-glucuronidation at the secondary N(1)HSO2 group. In a number of first-generation sulfonamides, N-acetylation produced a poorly soluble metabolite which may crystallize in the kidneys and was nephrotoxic. In contrast, N(1)-glucuronidation produces a soluble and nontoxic metabolite, as seen with sulfadimethoxine (4.205) whose N(1)-glucuronide accounted for 40 45% of a dose in humans [142] [146].
2228
Fig. 4.58. Among primary and secondary amines that are substrates of UGTs, we find drugs as well as a number of nonmedicinal xenobiotics, in particular, some industrial aromatic amines known to undergo toxification to mutagenic and carcinogenic metabolites [142] [147]. Interestingly, their N-glucuronidation may, in some cases, be involved in such toxification, witness the example of benzidine (4.206) shown here [148]. This xenobiotic can cause bladder cancer in humans, an organ-selective toxicity to be contrasted with the liver cancer selectivity prevailing in rats. The hepatic conjugation of benzidine by N-acetylation (see Chapt. 4.5) leads to N-acetyl- and N,Ndiacetylbenzidine (4.207 and 4.208, resp.). In humans, N,N-diacetylbenzidine (4.208) is a minor metabolite due to extensive deacetylation by hydrolases [3] [4] [107], whereas N-glucuronidation is an effective reaction yielding appreciable levels of benzidine Nglucuronide (4.209) and mainly of N-acetylbenzidine N-glucuronide (4.210). These two N-glucuronides are easily excreted via the kidneys, but their lability under even the slightly acidic conditions prevailing in the urinary tract results in their hydrolysis to benzidine (4.206) and N-acetylbenzidine (4.207), which will then be able to undergo oxidative toxification, in particular, by prostaglandin G/H synthase present at relatively high levels in bladder epithelium [2] [4] [149] [150]. The metabolic situation is different in rats, where a) N,N-diacetylbenzidine is a major metabolite which can be oxidized in the liver to reactive intermediates, and b) N-glucuronidation is minor.
2229
Fig. 4.59. The upper part of this Figure completes the previous Figure by drawing the readers attention to the role played by the N-hydroxy metabolites of carcinogenic aromatic amines. Indeed and as illustrated with naphthalen-1-amine (4.211), its metabolite N-hydroxynaphthalen-1-amine (4.212) [2] [4] [149] [150] is also a substrate of UGTs. Its glucuronidation proceeds mainly if not exclusively by reaction at the Natom rather than at the O-atom [142]. Like other N-glucuronides, the resulting conjugate 4.213 is excreted by the kidney and undergoes acid hydrolysis in urine, followed by toxification to the ultimate electrophilic carcinogen [2] [4] [151]. The other examples in the Figure are of medicinal interest. Norverapamil (4.214) is the Ndemethylated metabolite of the cardiovascular drug verapamil [152]. Like a number of similar N-dealkylated metabolites of medicinal tertiary amines [147], it is Nglucuronidated in humans and rats. The case of the antiepileptic agent D-23129 (4.215) is particularly interesting, since the compound contains both a primary and a secondary amino group. Its oxidative metabolism was minimal in human liver microsomes and liver slices, in contrast to N-glucuronidation which produced the two regioisomeric glucuronides 4.216 and 4.217 [153].
2230
Fig. 4.60. As shown in Fig. 4.37, a number of tertiary arylalkylamines can be glucuronidated to form N-quaternary glucuronides (also known as N -glucuronides). This permanent positive charge together with the high acidity of the carboxylate group (pKa ~ 3; see Fig. 4.36) result in such conjugates being zwitterions. Many substrates of N -glucuronidation are medicinal N,N-dimethylated arylalkylamines such as antihistamines and neuroleptics [142] [147] [154]. This is illustrated here with the nonsteroidal antiestrogen tamoxifen (4.218). This compound and its active 4-OH metabolite (not shown) both form an N -glucuronide (4.219 in the case of tamoxifen). For both substrates, the reaction in human liver microsomes was catalyzed exclusively by UGT1A4 among all UGTs tested [155]. In contrast, all tested UGTs, except 1A3 and 1A4, catalyzed the O-glucuronidation of 4-hydroxytamoxifen, showing that even a modest structural change may alter the substrate specificity of transferases. The second important group of arylalkylamines forming N -glucuronides are N-methylpiperidines and -piperazines, as exemplified here with the antipsychotic drug clozapine (4.220). Interestingly, this compound yields two direct N-glucuronides in humans, namely the quaternary N-glucuronide (4.221) and the N(5)-glucuronide (4.222) [156]. Both were excreted by patients administered the drug, and both were formed by incubation with human liver microsomes. The stability of the two N-glucuronides differed markedly; whereas 4.221 was hydrolyzed by glucuronidases and resistant to acid hydrolysis, 4.222 was resistant toward enzymatic hydrolysis but was labile under acidic conditions.
2231
Fig. 4.61. Another important group of substrates of N -glucuronidation are pyridines, i.e., compounds containing a pyridine ring. A typical substrate is (S)-nicotine (4.41) whose N-methylation was discussed in Fig. 4.15. Indeed, the natural (S)-nicotine (and its lactam metabolite (S)-cotinine resulting from 5-oxidation; not shown) are N glucuronidated by human UGT1A4 and to some extent also by UGT1A9 [32] [157]. Nicotine N -glucuronide (4.223) and cotinine N -glucuronide are found in the urine of smokers, with large quantitative differences depending on the activity of the many enzymes involved in the metabolism of nicotine. The second example in the Figure is that of indinavir (4.224), a well-known HIV protease inhibitor. This drug features a pyridine ring which undergoes N-oxygenation and N -glucuronidation [158]; both are major routes of metabolism in human liver slices and in vivo. The N -glucuronide showed a marked species dependence in that it was formed in monkeys but not in dogs or rats. Our last example here is that of a xenobiotic, namely the tobacco smoke component 4-(methylnitrosamino)-1-(pyridin-3-yl)butan-1-one (4.225; NNK). In most tissues, this compound undergoes carbonyl reduction to 4-(methylnitrosamino)-1(pyridin-3-yl)butan-1-ol (4.226; NNAL). Both compounds are potent lung carcinogens following the oxidative toxification of their nitrosamino group. Alternative metabolic routes may thus lead to detoxification, as is the case with the glucuronidation of NNAL. Interestingly, both N - and O-glucuronidation occur in humans, with the two glucuronides, 4.227 and 4.228, respectively, each accounting for ca. 1/4 to 1/3 of the total NNAL excreted in the urine of smokers [159]. N -Glucuronidation is catalyzed in humans by UGT1A4; rats form the O-glucuronide only, a reaction catalyzed by UGT2B1.
2232
Fig. 4.62. Besides the pyridine derivatives, a marked number of aromatic diaza- and polyazaheterocyclic compounds are known to undergo N-glucuronidation. Their interest lies in the fact that both N- and N -glucuronides may be formed when tautomerism is possible. Tautomerism is structurally excluded in the imidazole antifungal drug tioconazole (4.229), and indeed only the quaternary N-glucuronide (4.230) is formed, being a major urinary metabolite in humans [160]. The same reaction has been seen in a variety of N-aryl- or N-arylalkyl-substituted imidazoles, with UGT1A4 catalyzing their glucuronidation [161]. Polyazaheterocycles having an endocyclic NH (i.e., unsubstituted) moiety yield tertiary N-glucuronides, as illustrated with the methyl-1,1-biphenyl derivatives 4.231, 4.233, and 4.236 used as model compounds [162]. Compounds 4.231, 4.233, and 4.236 contain an 1H-imidazole, a 1,2,3triazole, and a tetrazole ring, respectively. The tertiary N-glucuronides 4.232, 4.234, 4.235, and 4.237 were formed in human, monkey, dog, and rat liver microsomes at an Natom distant from the substituted C-atom, presumably due to steric hindrance. The 1,2,3-triazole ring (in 4.233) and the tetrazole ring (in 4.236) have two such distal Natoms; they are distinct in 4.233 and identical in 4.236, explaining why the former yields two N-glucuronides (i.e., 4.234 and 4.235), while the latter yields one (i.e., 4.237). Note that the tetrazole ring is of particular interest in medicinal chemistry, being an acidic group (pKa ~ 5) used as isostere of a carboxylic group in, e.g., angiotensin II receptor antagonists (sartans). The N-glucuronide 4.232 was resistant to enzymatic and chemical hydrolysis, whereas 4.234, 4.235, and 4.237 were labile. It can be hypothesized that Nglucuronide lability increases with the acidity of the target N-atom in the substrate.
2233
Fig. 4.63. Here, we look in more detail into the problem of tautomerism. JNJ-10198409 (4.238) is a novel candidate under development with promises as an antitumor agent acting by a combination of anti-angiogenetic and antiproliferative properties [163]. As shown, the compound exists as two major tautomers at the pyrazole ring, namely the 1H- and the 2H-tautomers. The exocyclic N-atom may also be involved in a minor tautomeric equilibrium, but this is not considered here. Both tautomers at the pyrazole ring appear to be substrates of UGTs, as deduced from the formation of the tertiary N(1)-glucuronide, 4.239, in human, monkey and rat liver microsomes, and of the tertiary N(2)-glucuronide, 4.240, in rat liver microsomes (but not in human and monkey liver microsomes). Needless to say, these two N-glucuronides are different chemical entities that do not interconvert. A third glucuronide was formed in human, monkey, and rat liver microsomes, namely the N-glucuronide 4.241 which, as shown, has its two pyrazole N-atoms free to undergo tautomerism. The three N-glucuronides differed also in their chemical stability, since 4.240 and 4.241 were sensitive to enzymatic (bglucuronidase) and chemical hydrolysis, whereas 4.239 was stable. Perhaps differences in basicity can explain this contrast.
2234
Fig. 4.64. A case simultaneously comparable and different from the previous one is found with the anticonvulsant drug lamotrigine (4.242) [164]. This compound contains five N-atoms arranged in a diaminotriazine system, two of which are targets for Nglucuronidation. This pathway is the major route of metabolism of lamotrigine (4.242) in humans, who excrete in their urine ca. 80% of a dose as the quaternary N(2)glucuronide, 4.243. The remainder of the dose is excreted as the secondary N(5)glucuronide, 4.244, the quaternary N(2)-methyl derivative, the N(2)-oxide, and the unchanged drug plus unidentified metabolites. Inspection of the structure of 4.242 reveals three possible amino > imino tautomeric equilibria, one of which is shown. None of the resulting imino tautomers appears favored over the aromatic diaminotriazine structure, yet their possible role during the catalytic phase cannot be discounted. A further factor with 4.242 is the possibility for its quaternary N(2)glucuronide, 4.243, to deprotonate to a tertiary N-glucuronide as shown. We are not aware of any experimental evidence revealing the basicity of the N(2)-glucuronide or supporting the presence of its deprotonated form, but such information might be informative in terms of catalytic mechanism and excretion.
2235
Fig. 4.65. Some examples of S-atom glucuronidation are reported in the literature, in line with the occurrence of S-glycosides as natural products. An early example of the Sglucuronidation of a xenobiotic is that of the hepatotrophic agent malotilate (4.245). This compound is first transformed to the dithiol metabolite 4.246 which is then Sglucuronidated. The resulting S-glucuronide 4.247 was excreted as a major biliary metabolite in rats [165]. A recent example is that of the nonsteroidal progesterone receptor agonist tanaproget (4.248). Its S-glucuronide 4.249 has been characterized unambiguously and was a major metabolite ( > 10%) in human and rat liver microsomes [166]. The formation of this metabolite implies a tautomeric equilibrium between the oxazine-2-thione moiety and its iminothiol species. Xenobiotic C-glucuronidation is an even rarer reaction than S-glucuronidation and involves very few acidic CH moieties. The best known example is that of the uricosuric drug sulfinpyrazone (4.250), which features an acidic C(4)H group (pKa ~ 2.5) in the pyrazolidine-3,5-dione ring. The glucuronidation of 4.250 is a major metabolic reaction in humans, yielding conjugate 4.251 in which the C(4)-atom is linked to b-d-glucuronic acid via a CC bond [167]. The same reaction was seen in analogues (e.g., phenylbutazone) and at an activated acetylenic group.
2236
Fig. 4.66. The catalytic spectrum of UDP-glucuronosyltransferases is not limited to UDP-glucuronic acid as cofactor, since several among these enzymes are able to use UDP-glucose and transfer d-glucose to the substrate, thereby forming b-d-glucosides [95]. There are also reports of UDP-galacturonic acid being a cofactor of UGTs [168]. Furthermore, glycosylations may involve enzymes others than UGTs, as suggested by the formation of xenobiotic a-d-glucosides by rat liver a-glucosidases [169]. A few anecdotical reactions have also been reported, such as lactose conjugates of antibacterial sulfonamides in the milk of lactating dairy cows [170]. Fast development in analytical and structural techniques, coupled with the multidisciplinary science known as metabonomics, allow ever smaller traces of metabolites to be characterized and is expected to reveal yet other unexpected conjugates [171]. Mycophenolic acid (4.253) offers a nice example of glucosidation reactions [172]. This antineoplastic and immunosuppressant agent is the active metabolite of the prodrug mycophenolate mofetil (4.252). Mycophenolic acid (4.253) contains two target sites for UGTs, namely its phenol and COOH groups. Its phenol O-glucuronide 4.254 was the primary metabolite in the plasma of patients treated with the prodrug. The acyl glucuronide 4.255 and the phenol O-glucoside 4.256 were also characterized. Mycophenolic acid Oglucuronidation was catalyzed by all recombinant UGTs tested, and the O-glucuronides 4.254 and 4.255 were formed in microsomes from various human tissues. The same was true for the phenol O-glucoside 4.256. In addition, human kidney microsomes produced the acyl glucoside 4.257.
2237
Fig. 4.67. Two examples of xenobiotic O-glucosidation are presented here. Dogs administered cannabidiol (4.258; CBD) produced a range of oxidized metabolites, notably 4-hydroxy-CBD, 5-hydroxy-CBD, and 6-oxo-CBD [173]. These metabolites were the O-glucosidated (e.g., 4-hydroxy-CBD O-glucoside; 4.259) and excreted as major urinary metabolites. Our second example is that of bis(2-ethylhexyl) phthalate (4.260) [174]. Plasticizers in the chemical class of phthalates are suspected of being endocrine disruptors, hence the interest in their biotransformation. When administered to mice, bis(2-ethylhexyl) phthalate (4.260) was oxidized on one of its 2-ethylhexyl side chains to a secondary alcohol, a ketone and a carboxylic acid, while the other side chain was cleaved by hydrolysis. The carboxy group so liberated became available for conjugation, yielding three acyl glucosides which were characterized in the animals urine. One of these three acyl glucosides was the conjugate 4.261.
2238
Fig. 4.68. Reactions of N-glucosidation seem to be somewhat better documented than reactions of O-glucosidation, with a marked preference for acidic NH groups [175]. Typical substrates are barbiturates, which were the subject of a number of informative studies published several years ago [176] [177]. Thus, phenobarbital (4.262) is conjugated to its N-glucoside 4.263 as a minor urinary metabolite in humans, where no N-glucuronidation of barbiturates occurs. Interestingly, C(5) in N-unsubstituted barbiturates is a prochirality center, to be transformed into a stereogenic center by a reaction of N-glucuronidation or N-glucosidation. Given that sugars are chiral, barbiturate N-glucuronides and N-glucosides will exist as two diastereoisomers [178], as illustrated here. Product stereoselectivity is documented in this reaction of conjugation, with (5S)-phenobarbital N-glucoside being the preferred product of human UGTs (probably UGTs in the 2B subfamily). Among mammals, only the mouse showed a capacity to N-glucuronidate barbiturates comparable to that of humans. In the mouse, phenobarbital N-glucuronide was excreted in several-fold higher amount than phenobarbital N-glucoside, and product stereoselectivity in Nglucosidation was the opposite of that in humans. Our second example is ranirestat (4.264), a new aldose reductase inhibitor [179]. This compound has a succinimide ring analogous to the barbiturate ring, and it undergoes both N-glucosidation and Nglucuronidation in humans. However, human UGTs of the 2B subfamily catalyzed only the former reaction. Note that, like the barbiturate ring, the succinimide ring in ranirestat (4.264) is labile to chemical hydrolysis followed by decarboxylation, and indeed its sugar conjugates were characterized as the ring-opened metabolites 4.265.
2239
Fig. 4.69. The case of the new xanthine oxidoreductase inhibitor FYX-051 (4.266) illustrates again the interplay of tautomerism and N-glycosylation [180]. The compounds exists as the 1H- and 2H-tautomers as shown, and both NH groups are target of UGTs, with a consistent preference for conjugation at the N(1)-atom. Both the N-glucuronides, 4.267 and 4.268, and the N-glucosides, 4.269 and 4.270, were formed, but large species differences were seen. Little N-glucuronidation and Nglucosidation occurred in rats. N-Glucuronidation (but no N-glucosidation) was seen in humans and monkeys, while N-glucosidation was predominant in dogs (see Part 6). Besides weakly acidic NH groups, there are very few reported cases of weakly basic amino groups being N-glucosidated. One example is 5-aminosalicylic acid (4.271), a drug used to treat inflammatory bowel disease [181]. Its major metabolite in humans is the N-acetyl conjugate (see Chapt. 4.5), but traces of the N-glucoside 4.272 were also seen. This conjugate was unstable in solution, and its formation was partly or totally nonenzymatic.
2240
Fig. 4.70. To conclude this important Chapter, we summarize some of the properties of glucuronidation and glucuronides, keeping in mind that the statements made here are not rules but mere generalizations having numerous exceptions. From a pharmacological and pharmacokinetic viewpoint, the really significant reactions in this Chapter are the glucuronidations of hydroxy, carboxy, and amino groups. This neat classification does not correspond to well-defined families or subfamilies of UDP-glucuronosyltransferases, and yet major species differences are apparent (see Part 6). The respective products of these reactions, namely O-glucuronides, acyl glucuronides, and N-glucuronides, differ greatly in their stability. Thus, O-glucuronides are consistently good substrates of b-glucuronidases and may undergo enterohepatic cycling when of sufficient molecular weight to be excreted in the bile. As a rule, acyl glucuronides are reactive molecules undergoing rearrangement and forming adducts with blood and tissue proteins. As for the N-glucuronides, they are usually stable toward b-glucuronidases and labile under acidic conditions, but a number of exceptions have been mentioned in this Chapter. A subclass of N-glucuronides are the quaternary N-glucuronides; their permanent positive charge renders them zwitterionic and may be hypothesized to affect their recognition by anion transporters.
2241
Fig. 4.71. In this Chapter, we focus on reactions of acetylation. Compared to sulfonations and glucuronidations, they are modest in terms of the number and variety of substrates, but remain significant in a toxicological perspective [5 7] [182]. As far as xenobiotic metabolism is concerned, three reactions of acetylation are known, namely N-acetylations, O-acetylations, and N,O-acetylations. The former two types of reactions use acetyl-coenzyme A (abbreviated acetyl-CoA or AcCoA; 4.273) as acetyl donor and are shown here. N-Acetylations involve mainly primary aromatic amines, hydrazines, and hydrazides, in other words, weakly basic or non-basic NH2 groups. However, some basic arylalkylamines are also N-acetylated. The xenobiotic substrates of O-acetylation are aromatic hydroxylamines of toxicological significance. Reactions of N,O-acetylations are not shown here and will be discussed separately, being enzymecatalyzed reactions of trans-acetylation whose acetyl donor is a xenobiotic arylacetamide. Coenzyme A (4.274) is an essential cofactor in the metabolism of lipids; we will encounter it again in Chapt. 4.6 where it will be shown to play a critical role in significant yet lesser known reactions of conjugation. As shown here, coenzyme A results from the conjugation of adenosine 3-phosphate 5-diphosphate with (R)pantothenic acid (in the larger oval) and cysteamine (in the smaller oval). The catalytically essential group in coenzyme A is the thiol, which forms a reactive thioester group with acyl moieties such as acetyl (i.e., in 4.273).
2242
Fig. 4.72. The acetylation of xenobiotics is mainly a reaction of N-acetylation. The major enzyme here is arylamine N-acetyltransferase (NAT), which targets primary aromatic amines and hydrazines [8] [10] [182 185]. Two genes exist in humans, whose products show different yet partly overlapping substrate specificities. Both the NAT1 and NAT2 enzymes are polymorphic, the latter distinctly more than the former. Some large species differences have been reported in substrate specificities. Also noteworthy is the fact that the mouse has three Nat genes and three functional enzymes (Nat1, Nat2, and Nat3), with the mouse Nat1 being functionally analogous to the human NAT2 [186]. The second enzyme in this Figure is arylalkylamine N-acetyltransferase, the product of the AANAT gene. Its distribution is markedly restricted compared to NAT, and its preferred substrates are arylethylamines. Several of these substrates are physiological compounds such as neurotransmitters, hence the name serotonin Nacetyltransferase. A number of xenobiotic basic amines have also been reported, as we shall see.
2243
Fig. 4.73. A number of acetyltransferases catalyze the O-acetylation of alcoholic groups in endogenous compounds, the best known of which is choline O-acetyltransferase (EC 2.3.1.6; human gene CHAT) which synthesizes the neurotransmitter acetylcholine [8]. Another O-acetyltransferase of physiological significance is carnitine O-acetyltransferase (EC 2.3.1.7; human gene CRAT). However, and to the best of our knowledge, no O-acetylation of xenobiotics has been documented in mammals except of N-arylhydroxylamines and N-aryl-N-hydroxyacetamides (also known as N-arylhydroxamic acids). The two enzymes presented here are the ones catalyzing the O-acetylation of such xenobiotics, but they represent enzymatic activities rather than distinct proteins. Indeed, much evidence points to arylamine Nacetyltransferases (EC 2.3.1.5) as the enzymes catalyzing these reactions. The literature appears rather consistent in assigning acetyl-coenzyme A-dependent O-acetylations of N-arylhydroxylamines and N-arylhydroxylamides to mainly EC 2.3.1.118, and N-arylN-hydroxyacetamide-dependent N,O-transacetylations to EC 3.2.1.56 [8].
2244
Fig. 4.74. Several primary arylamines of medicinal interest are known to be good substrates of NAT in humans. This is the case of para-aminobenzoic acid (NAT1) and 5aminosalicylic acid (4.271; see Sect. 4.4.9 above) (NAT1 % NAT2) [181] [182]. Other drugs include the antileprosy agent dapsone (Fig. 2.67 in Part 2 [2]), and various antibacterial sulfonamides. Thus, sulfamonomethoxine (4.275) was extensively N(4)acetylated in humans to metabolite 4.276 (ca. 35 38% of a dose), whereas N(1)glucuronidation was low (ca. 11 13%). Unchanged drug accounted for ca. 13 14%, leaving ca. 35 40% of a dose unaccounted for [187]. There was no difference between slow and fast acetylators (NAT2 phenotypes, see Part 6), suggesting NAT1 to be the enzyme involved in the reaction. Its low glucuronidation-to-acetylation ratio distinguishes sulfamonomethoxine (4.275) from sulfadimethoxine (4.205; see Fig. 4.57). Our second example deals with a nonsteroidal androgen receptor modulator bearing an NAc substituent, namely (S)-3-[4-(acetylamino)phenoxy]-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide (4.277) [188]. This agent is deacetylated in humans to the primary arylamine 4.278, an active metabolite back-acetylated to the parent compound 4.277. N-Acetylation of 4.278 was indeed fast in human liver cytosol (NAT2 > NAT1) and in rats (in vivo and in vitro), but did not occur in dogs. An even more complex case is seen with levosimendan (4.279) developed for the treatment of congestive heart failure [189]. Two plasma metabolites have been characterized in humans, the arylamine 4.280 produced by a reductive reaction catalyzed by intestinal bacteria, and the N-acetylated metabolite 4.281 likely produced by NAT2. Interestingly, the latter metabolite has a pharmacological activity similar to that of the parent drug.
2245
Fig. 4.75. Hydrazines and hydrazides are good and highly selective substrates of human NAT2 [182]. Few such compounds are used as drugs, two of which are shown here. Besides undergoing oxidation reaction, the antihypertensive agent hydralazine (4.282) is extensively conjugated in humans (NAT2) and other species to its N-acetyl metabolite [190]. Earlier studies yielded contradictory results regarding the nature of this metabolite, until further studies proved its structure to be 3-methyl[1,2,4]triazolo[3,4-a]phthalazine (4.283). The latter product derives from the N-Ac intermediate, which is unstable and spontaneously cyclizes to 4.283 presumably via its enol tautomer. The antituberculosis drug isoniazid (4.284) is another good substrate of human NAT2, and one whose N-acetylation to the inactive conjugate 4.285 shows significant quantitative difference between fast and slow acetylators [191] [192]. The problem is complicated by the fact that 4.284 also undergoes hydrolase-catalyzed hydrolysis to hydrazine (4.286), a toxic xenobiotic used in particular as a rocket propellant. It appears that at least part of the hepatotoxicity and neurotoxicity which threatens slow acetylators more than fast acetylators is due to free radicals derived from hydrazine (4.286) and its monoacetyl conjugate 4.287. In contrast, the subsequent formation of 1,2-diacetylhydrazine (4.288) is a reaction of detoxification.
2246
Fig. 4.76. In Sect. 4.3.5, we encountered the N-sulfonation of trovafloxacin (4.117) to the sulfamate 4.118. This antibacterial agent of the quinolone class is of further interest, since its metabolism is almost exclusively by conjugation in humans and rats, with no Phase-I metabolite being reported. This is presumably due to the steric and electronic shielding of CYP target groups in the molecule. Formation of the N-acetyl metabolite 4.289 and acyl glucuronide 4.290 were the two additional pathways in these two species, with acyl glucuronidation being the major one [78]. The situation in dogs was more complex, with two minor Phase I metabolites being seen, and the N-Ac conjugate 4.289 seemingly being produced by the intestinal microflora. Independently of its formation in the liver or intestine, this N-Ac conjugate 4.289 is an interesting metabolite, since it is one among a rather limited number of known examples of the N-acetylation of a basic amino group. While we are not aware of secondary arylamines being acetylated, rare cases of acetylation of secondary basic amines are known.
2247
Fig. 4.77. Another example of the N-acetylation of a primary basic amine is found in the metabolism of the b-adrenoceptor blocker propranolol (4.161; see also Sect. 4.4.2). In this case, however, conjugation involves a metabolite (i.e., the primary amine 4.291) rather than the parent drug. Indeed, 2 4% of a dose of 4.161 were accounted for by Nacetyl-N-desisopropylpropranolol (4.292) in the urine of humans administered the drug [193]. There were indications that the total formation of the conjugate may have been even higher given its further oxidative metabolism. Another interesting finding is the evidence that NAT1 was the enzyme involved in the reaction. The N-acetylation of acidic NH2 groups is also documented in a few cases. This is the case of the anticonvulsant agent zonisamide (4.293), whose N-Ac conjugate, 4.294, accounted for ca. 8% of a dose in rats, and was a minor metabolite in humans [194]. It is interesting to note that when acetylation targets slightly acidic NH2 groups (pKa of zonisamide is ca. 10), it increases acidity and hence ionization and hydrosolubility (pKa of Nacetylzonisamide is ~ 5). This contrasts with the acetylation of basic groups, where basicity is canceled. A different example is provided by cyanamide (4.295), a potent inhibitor of aldehyde dehydrogenase and an alcohol deterrent used as the citrated calcium salt. Cyanamide (4.295) is isoelectronic with the sulfonamido group, and its acidic amino group is a good target of N-acetyltransferases [195]. N-Acetylcyanamide (4.296) is the major metabolite of cyanamide in humans, rabbits, rats, and dogs. This last finding was largely unexpected, given that dogs as a rule are poor acetylators.
2248
Fig. 4.78. A number of industrial arylamines are known for their carcinogenic potential, following metabolic toxification in which reactions of N- and O-acetylation have a role to play [183b] [196 198]. As summarized here using fluoren-2-amine (4.297) as a prototypal example, such xenobiotic arylamines can be N-oxidized to an Narylhydroxylamine (e.g., 4.299) by cytochromes P450 (mainly CYP1A2) or the peroxidase function of prostaglandin G/H synthase (see Part 2). O-Sulfonation to 4.301 (Chapt. 4.3) or NAT-catalyzed O-acetylation to 4.302 (R H) forms a labile ester able to undergo heterolytic cleavage to form a highly reactive, adduct-forming nitrenium cation 4.303 (R H). Interestingly, quantum-mechanical calculations have shown that the heterolytic cleavage of an N,O-sulfate ester is markedly easier when the hydrogen sulfate anion (HOSO ) rather than the sulfate anion (SO2 ) is the leaving group [198]. 3 4 This appears linked to the bladder carcinogenicity of several such arylamines. The reactions so far discussed are marked with red arrows to signify that they are the preferred pathways of toxification of carcinogenic arylamines. Indeed, direct Nacetylation of xenobiotic arylamines to form, e.g., 4.298, is considered in a number of cases to be a reaction of detoxification. Nevertheless, the possibility remains in other cases of N-oxidation of an arylacetamide to an N-aryl-N-hydroxyacetamide such as 4.300. The latter can also be activated to a reactive O-sulfate or O-acetate, and ultimately to a nitrenium cation (e.g., 4.301, 4.302, and 4.303, resp.; R Ac). One important reaction is not explicit here, namely N,O-acetylation whose mechanism is presented in more details in the next Figure.
2249
Fig. 4.79. Like the O-acetylation of xenobiotic N-arylhydroxylamines ( NHOH) and N-arylhydroxylamides (arylhydroxamic acids; N(OH)acyl), the reactions of N,Oacetylation (in fact, N,O-transacetylations) are catalyzed by arylamine acetyltransferases. However, the nature of the Ac donor in reactions of N,O-acetylation differs from that in N- and O-acetylations [199]. To help the reader, we begin here by summarizing in Box A the reactants and products of O-acetylation, where the Ac moiety is transferred from acetyl-CoA to a generic N-arylhydroxylamine 4.304, the products being the generic O-acetyl-N-arylhydroxylamine 4.305 and coenzyme A. In contrast, the Ac donor in reactions of N,O-acetylation (Boxes B D) is an N-aryl-Nhydroxyacetamide, 4.306, which transfers its Ac group to a cysteinyl residue in the enzyme protein, thus forming an acetyl thioester (NAT-S-acetyl) and liberating the Narylhydroxylamine 4.307 (Box B). Two options exist following this first step. In the intramolecular reaction of N,O-acetylation (Box C), the N-arylhydroxylamine 4.307 just formed remains bound to the enzyme and captures the acetyl group to yield the Oacetyl-N-arylhydroxylamine 4.308. In the intermolecular reaction of N,O-acetylation (Box D), another N-arylhydroxylamine, 4.309, binds to the enzyme and is acetylated to the O-acetyl-N-arylhydroxylamine 4.310.
2250
Fig. 4.80. In Part 3, we illustrated the fatty acyl esterification of low-molecular-weight alcohols such as ethanol. These reactions are independent of coenzyme A and catalyzed by hydrolases (EC 3) such as fatty-acyl-ethyl ester synthase (FAEES). Mention was made of the different esterification pathways open to large lipophilic alcohols, mainly endogenous and exogenous steroids, which we briefly present here [8] [200]. The major enzyme involved in the fatty acyl esterification of such steroids is sterol O-acyltransferase (EC 2.3.1.26; cholesterol acyltransferase (ACAT)), a microsomal enzyme of which two genes (SOAT1 and SOAT2) exist in humans. Another enzyme catalyzing the same reaction is lecithin:cholesterol acyltransferase (EC 2.3.1.43; human gene LCAT) found in blood serum, and whose acyl donor is not acyl-CoA but a phospholipid [201]. Our first illustration is 17b-estradiol (4.18) which we encountered earlier in connection with catechol O-methylation (Sect. 4.2.1) and glucuronidation (Sect. 4.4.1). This endogenous steroid is also frequently used as a drug; its conjugation to fatty acids such as palmitic, stearic, oleic, palmitoleic, linoleic, and arachidonic acids has been demonstrated in rat liver microsomes supplemented with the corresponding acyl-CoA [202]. Such highly lipophilic metabolites (e.g., the oleyl conjugate 4.311) are stored in tissues and act as natural slow delivery devices. The same is true of the antiasthmatic glucocorticoid budesonide (4.312) [203]. Its incubation in ATP- and CoA-fortified human lung and liver microsomes yielded a variety of fatty acyl conjugates such as the palmitic ester 4.313. Following its inhalation, budesonide is extensively conjugated and retained as fatty acyl esters in airway tissues from which it is slowly released by hydrolysis, explaining its long duration of action.
2251
Fig. 4.81. The coupling of xenobiotic acids to coenzyme A, and the numerous metabolic pathways open to such acyl-CoA cofactors, form a complex and insufficiently understood field of research at the interface of lipid biochemistry and xenobiotic metabolism [204]. The key compound here is coenzyme A (4.273 in Fig. 4.71), on which both the previous Chapt. 4.5 and the present one are centered [205]. However, there is a major difference between the two Chapters, as schematized in this introductory Figure. Whereas the previous Chapter dealt with endogenous acids (acetic acid and fatty acids) bound to coenzyme A and transferred to a xenobiotic acceptor, the present Chapter has xenobiotic acids as substrates. Their conjugation to coenzyme A is catalyzed by ligases, yielding xenobiotic acyl-CoA cofactors which are a crossroads to an unusual variety of further metabolic pathways, most or all of which are catalyzed by enzymes whose physiological function is in lipid biochemistry. These pathways will be presented, in turn; many of them are synthetic (anabolic) ones, an obvious exception being b-oxidation. Before discussing these pathways according to the classification shown, we examine the ligases involved in xenobiotic acyl-CoA formation and some properties of the resulting cofactors.
2252
Fig. 4.82. The coupling of carboxylic acids to coenzyme A is catalyzed by enzymes known as acid-thiol ligases (EC 6.2.1), three of which play a leading role in forming xenobiotic acyl-CoA cofactors [204 207]. As shown, these are the short-chain acylCoA ligase, the medium-chain acyl-CoA ligase, and the long-chain acyl-CoA ligase, which includes one or more very long-chain acyl-CoA ligases. There is an overlap in the substrate specificity of these enzymes, all the more so, since they are in fact families with various isozymes as documented by the human genes reported in the Figure. The subcellular and tissular localizations differ among enzymes. The enzymatic reactions take their energy from the splitting of ATP into AMP and pyrophosphate, with the magnesium cation acting as a cofactor in the reaction. As we shall see, a large variety of xenobiotic carboxylic acids are substrates of these ligases, but each of the resulting acylCoA conjugates is then processed by only a few among the pathways depicted in the previous Figure.
2253
Fig. 4.83. The main focus of this Chapter is on the metabolic reactions typical of xenobiotic acyl-CoA cofactors. In addition and as a result of their intrinsic reactivity [208], acyl-CoA conjugates also undergo a variety of reactions summarized in this Figure. Thus, acyl-CoA thioesters react as electrophiles with H2O (chemical hydrolysis) and with glutathione (see Chapt. 4.7) to form glutathione conjugates as shown [209]. Interestingly, a series of xenobiotic acyl-CoA conjugates revealed a correlation between their rates of hydrolysis and their rates of transacylation with glutathione [209a]. Acyl-CoA conjugates are also specific substrates of acyl-CoA thioesterases (EC 3.1.2.1 and mainly 3.1.2.2) [210]. A worrying property is the structure-dependent capacity of some xenobiotic acyl-CoA conjugates to react as electrophiles with proteins, thereby forming acylated proteins with immunogenic potential [211] [ 212]. On a more positive side, some xenobiotic acyl-CoA conjugates are pharmacologically active. Thus, the (S)-enantiomers of the well-known non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen and ketoprofen (see Sect. 4.6.4) are the active compounds that inhibit cyclooxygenase (COX), but there is proof that the acyl-CoA conjugate of the inactive (R)-enantiomers also contributes to the therapeutic effects by inhibiting COX-2 [213]. There is also evidence that clofibric acid and other fibrate drugs used as hypolipidemic peroxisome proliferators act as their acyl-CoA conjugates to inhibit fatty-acid synthesis [214]. Finally, the inhibition of fatty-acid b-oxidation is documented for some medicinal arylalkanoic acids, particularly profens; the mechanism of this inhibition does not involve their acyl-CoA conjugates but appears to be due to a combination of coenzyme A sequestration and direct inhibition of acyl-CoA ligases [205] [215].
2254
Fig. 4.84. In contrast to the acyl-CoA cofactors whose lability and metabolic intermediacy prevents their excretion from the body, most of the subsequent metabolites are sufficiently stable and hydrophilic to be excreted. Exceptions are the lipid and sterol conjugates, which are too lipophilic to be excreted. Here, we begin with amides formed from an endogenous amino acid and a xenobiotic acyl-CoA cofactor [206] [216]. The most common amino acid in such reactions is glycine, and its prototypal substrate is benzoic acid (4.314), more precisely its benzoyl-CoA cofactor [217]. The enzymes catalyzing the formation of N-benzoylglycine (4.315) are mainly glycine N-benzoyltransferase (EC 2.3.1.71) and glycine N-acyltransferase (EC 2.3.1.13; human genes GLYAT, GLYATL1, and GLYATL2). Note that N-benzoylglycine is better known under its trivial name hippuric acid, since it was first characterized in 1829 by Liebig in the urine of horses [218]. Hippuric acid (4.315) is thus considered by many to be the first xenobiotic metabolite ever characterized. Numerous ringsubstituted derivatives and analogues of benzoic acid form a glycine conjugate [219], giving insight into informative structure metabolism relationships [132] [220]. Further examples of medicinal interest include the hypolipidemic drug nicotinic acid (4.316) whose conjugation to N-nicotinoyl glycine (4.317; nicotinuric acid) is a major metabolic pathway [221]. The same is true for acetylsalicylic acid (4.318, Aspirin); in humans, over 90% of a dose is hydrolyzed to salicylic acid (4.192), most of which (depending on the dose) is eliminated as salicyluric acid (4.319) [222].
2255
Fig. 4.85. The previous Figure suggests that only benzoic acids and small analogues yield glycine conjugates in humans. This appears indeed as a rule, allowing for possible exceptions (see later). In contrast, the formation of glutamine conjugates presented here favors larger substrates. Two enzymes are the main catalysts of the reaction, namely glutamine N-phenylacetyltransferase (EC 2.3.1.14) which shows a broad substrate specificity, and glutamine N-acyltransferase (EC 2.3.1.68) which does not act on benzoic acids. Our first example is 4-phenylbutanoic acid (4.320), an effective drug used in patients with hyperammonemia due to inborn errors in urea synthesis. Indeed, the metabolism of 4-phenylbutanoic acid (4.320) helps nitrogen excretion in the form of its glutamine conjugate 4.321, a major metabolite in humans (20 25% of a dose) [223]. There is more to the metabolism of this drug, since it undergoes C2 chain shortening by b-oxidation (see Sect. 4.6.4) to form 2-phenylacetic acid also excreted as the glutamine conjugate 4.322 (30 35%). These metabolites are not formed in the rat, which produces high levels of acyl glucuronides, plus N-(2-phenylacetyl)glycine (4.323) not found in humans. The Figure also shows one of the many metabolic pathways of the antiepileptic drug valproic acid (4.324). This compound formed only traces of its glycine conjugate in epileptic patients, while its glutamine conjugate 4.325 and glutamic acid conjugate 4.326 were produced in somewhat higher amounts [224]. The latter metabolite is a unique observation in humans, being formed either by conjugation with glutamic acid or by deamidation of the glutamine conjugate.
2256
Fig. 4.86. Taurine (H2NCH2CH2 SO3H) is another amino acid which, together with glycine, shares an important physiological function in the conjugation of biliary acids. In humans, the conjugation of bile acid-CoA with taurine or glycine is catalyzed by the cytosolic enzyme bile acid-CoA:amino acid N-acyltransferase (EC 2.3.1.65; human gene BAAT) [8] [225]. There have been a number of recent reports of xenobiotic carboxylic acids yielding taurine conjugates. Thus, 2-(4-chloro-2-methylphenoxy)acetic acid (4.327), a plant growth regulator used as herbicide, formed both the taurine conjugate 4.328 and the glycine conjugate 4.329 [226]. Both metabolites were of marked importance in the dog. In contrast, no taurine conjugate and only traces of the glycine conjugate were formed and excreted in rats, which excreted most of a dose unchanged. Another interesting example is that of MRL-II (4.330), an agonist of the a-peroxisome proliferator-activated receptor (aPPAR) of interest as a cholesterol- and triglyceridelowering agent [227a]. When administered to dogs, dose-dependent amounts of the acylglucuronide and taurine conjugates were excreted in the bile. Low doses favored the taurine conjugate, whose proportion decreased at higher doses. In contrast to 2-(4chloro-2-methylphenoxy)acetic acid (4.327), the retinoid X-receptor ligand and antitumor agent targretin (4.331) did form taurine conjugates in rats from the unchanged drug and from two oxidized metabolites [227b]. There are few reports of xenobiotic taurine conjugates being formed in humans. One nice example is that of the NSAID ibuprofen (4.332). Its taurine conjugate 4.333 was a minor urinary metabolite (1 2% of a dose) excreted almost exclusively as the (S)-enantiomer [228], in contrast to the withdrawn NSAID benoxaprofen whose taurine conjugate was mainly the (R)enantiomer in rats (see also Sect. 4.6.4).
2257
Fig. 4.87. The esters formed by the acylation of endogenous hydroxy compounds with xenobiotic acyl-CoA cofactors are summarized in Fig. 4.81. Based on their lipophilicity and resulting behavior in the body, the resulting conjugates are classified as more lipophilic than the parent xenobiotic carboxylic acids (hybrid lipid, sterol esters, and ethyl esters), or more hydrophilic (carnitine esters). Here, we summarize the major types of mixed (i.e., hybrid) glycerides and sterol esters formed from xenobiotic acids [204] [229] [230]. The formation of hybrid triglycerides and sterol esters has been reported for a number of xenobiotic carboxylic acids using, e.g., human or animal hepatocytes or adipocytes [230]. In vivo evidence in animals is also available, mostly in rats [231]. These conjugates include hybrid triglycerides such as the generic dipalmitoylglyceride conjugate 4.334, hybrid phospholipids such as the generic 1-acyl2-palmitoyl-3-phosphocholine 4.335, and cholesteryl esters 4.336. There are also examples of xenobiotic carboxylic acids being coupled to the 3-OH group of bile acids [232]. A number of enzymes are known or believed to catalyze the formation of lipid conjugates, most notably diacylglycerol O-acyltransferase (EC 2.3.1.20; human genes DGAT1 and DGAT2), 2-acylglycerol O-acyltransferase (EC2.3.1.22; human genes MOGAT1, MOGAT2, and MOGAT3), 1-acylglycerophosphocholine O-acyltransferase 1 (EC 2.3.1.23; human gene PLCAT1), sterol O-acyltransferase (see Fig. 4.80), and acylglycerol-3-phosphate O-acyltransferases (EC 2.3.1.51 and -52; human gene root AGPAT) [8].
2258
Fig. 4.88. A marked number of xenobiotic carboxylic acids have been reported to form hybrid lipid conjugates [229 231], as illustrated here. Benzoic acid (4.314) is unusual, since the vast majority of known substrates are larger molecules. Several drugs are substrates, for example, the antiepileptic valproic acid (4.324), which was incorporated into phospholipids in cultured neurons [233]. Other drugs include NSAIDs such as ibuprofen (4.332) and ketoprofen [231], and some hypolipidemic drugs such as lifibrol (4.337) [234]. Some agrochemicals are also substrates, witness the herbicide 4-(2,4dichlorophenoxy)butanoic acid (4.338; 2,4-DB) [230]. In this case, triacylglycerol analogues were the major products formed in cultured adipocytes, while some mixed diacylglycerols and phosphatidylcholines (i.e., containing one fatty acid and one xenobiotic acid) were also observed. An example of cholesteryl ester formation is provided by the hypolipidemic agent 4-[10-(4-chlorophenoxy)decyloxy]benzoic acid (4.339) [235]. Following oral administration to rats, the cholesteryl ester was formed and accumulated in the liver, being neither metabolized further nor transported by lipoproteins. Accumulation in the liver and other tissues is certainly a factor of concern, as illustrated by the fate of fenvalerate (4.340) in rats and mice [236]. This pyrethroid insecticide exists as four stereoisomers. Following administration of the isomeric mixture, a lipophilic residue was identified in all analyzed tissues and found to be the cholesteryl ester of (2R)-2-(4-chlorophenyl)isovaleric acid (4.341). Remarkably, this conjugate was shown to be the causative agent of microgranulomatous changes in the liver of mice chronically fed fenvalerate (4.340). A few studies have investigated the rate of elimination of hybrid lipid conjugates from tissues and found it to be markedly slower than that of their natural counterparts [231b] [237].
2259
Fig. 4.89. There are only few examples of the coenzyme A-dependent esterification of xenobiotic carboxylic acids with short-chain alkanols. In fact and to the best of our knowledge, the only example of medicinal interest is that of etretinate (4.342), a highly teratogenic retinoid used cautiously for the treatment of severe psoriasis resistant to other forms of therapy. Etretinate is an ethyl ester prodrug whose hydrolase-catalyzed hydrolysis yields the active carboxylic acid known as acitretin (4.343). In patients under long-term therapy, plasma etretinate levels remain detectable for over two years following discontinuation of treatment, a pharmacokinetic result incompatible with effective hydrolysis and further degradation and elimination of acitretin (4.343) [238]. The explanation was found with the discovery that part of the metabolically formed 4.343 forms the acitretinoyl-CoA thioester conjugate 4.344, a reaction catalyzed by human liver microsomal long-chain fatty acid-CoA ligase (see Fig. 4.82). This thioester is then transesterified to etretinate by an insufficiently characterized ethanol acyltransferase which can also use other short-chain alkanols [239]. The resulting futile metabolic cycle is in fact far from pharmacologically futile, the highly lipophilic etretinate being stored in adipose tissues and serving as a reservoir for the active acitretin (4.343). Interestingly, the CoA-thioester 4.344 is also the intermediate in the formation of side-chain-shortened metabolites such as 4.345 (resulting from an initial C1 shortening in a 3-methyl-branched carboxylic acid a-oxidation) and 4.346 (resulting from subsequent C2 shortening b-oxidation; discussed below). As an aside, we note that another interesting metabolite of acitretin is (Z)-acitretin (4.347) whose reversible formation is presumably catalyzed by the retinoid cis-trans isomerases EC 5.2.1.3 and 5.2.1.7.
2260
Fig. 4.90. l-Carnitine ((R)-(3-carboxy-2-hydroxypropyl)(trimethyl)ammonium) is a d-amino acid whose essential role is to allow membrane translocation of fatty acids following their conjugation to acyl-carnitines. The formation of the latter is catalyzed by carnitine O-acyltransferases, in particular carnitine O-acetyltransferase (EC 2.3.1.7; human gene CRAT) which acts with C2 C10 alkanoic acids, carnitine O-octanoyltransferase (EC 2.3.1.137; human gene CROT) which acts with C4 C16 alkanoic acids, and carnitine O-palmitoyltransferase (EC 2.3.1.21; human genes CPT1A, CPT1B, CPT1C, and CPT2) having a broad substrate specificity in the C6 C20 range [8] [240]. While Gly, Glu, and taurine form amide conjugates with xenobiotic acids, carnitine forms esters via its OH group, since its trimethylammonium group is not available for conjugation. Another physicochemical characteristic of carnitine conjugates is the fact that the negative charge in the parent carboxylate anion is replaced by a zwitterionic function capable of forming an internal ionic bond. Two medicinal examples of carnitine conjugates are shown here. Valproic acid (4.324), whose capacity to form hybrid glycerides was presented above, also forms valproylcarnitine (4.348) as a minor metabolite in humans, as seen in the urine of epileptic patients treated with the drug [241]. The anti-inflammatory agent tolmetin (4.195), whose acylglucuronide was discussed in Chapt. 4.4, also forms amino acid conjugates. In rats, for example, the relative quantitative importance of conjugates was acyl glucuronide > taurine conjugate 4.349 > carnitine conjugate 4.350 > glycine conjugate [211a].
2261
Fig. 4.91. This Figure exemplifies cases where the substrate of carnitine conjugation is not the xenobiotic per se but a metabolite thereof. A medicinally relevant situation is that of pivampicillin (4.351), the (pivaloyloxy)methyl ester of the b-lactam antibiotic ampicillin (4.352). Bio-hydrolysis of pivampicillin liberates the promoiety pivalic acid (4.353), a known substrate of the carnitine conjugation pathway. However, the formation and excretion of pivaloylcarnitine (4.354) in humans and rats dosed with pivalic acid or pivampicillin is limited by the body reserves of carnitine. Humans supplemented with carnitine excreted up to 90% of the administered amount of pivalic acid as pivaloylcarnitine [242]. The second example is that of cycloprate (4.355), a miticide agent whose hydrolysis liberates cyclopropanecarboxylic acid (4.356). The latter is a good substrate of carnitine O-acetyltransferase, as shown in rats receiving high doses of cycloprate [243]. In rat hepatocytes, the substrate specificity of carnitine ester formation was cyclopropanecarboxylic acid (4.356) > cyclobutanecarboxylic acid > cyclohexanecarboxylic acid benzoic acid > pivalic acid.
2262
Fig. 4.92. In this last Section of Chapt. 4.6, we survey reactions of xenobiotic acyl-CoA conjugates that modify the acyl moiety by oxidizing it, lengthening its chain, or racemizing it. Most available examples concern b-oxidations, which in eukaryotes occur in peroxisomes (for very-long-chain fatty acids) and mitochondria, their physiological products being acetyl-CoA and ATP. Extensive investigations with wphenylalkanoic acids 4.358 have revealed that such xenobiotic carboxylic acids are also good substrates of the b-oxidation enzymatic machinery [8] [244] [245]. Thus, 12phenyllauric acid forms its CoA-conjugate (C12-4.358-CoA), a reaction catalyzed by long-chain acyl-CoA ligase (EC 6.2.1.3; see Fig. 4.82). The sequential b-oxidation steps involve 2,3-dehydrogenation catalyzed by acyl-CoA oxidase (EC 1.3.3.6), hydration to the (S)-3-hydroxyacyl intermediate catalyzed by enoyl-CoA hydratase (EC 4.2.1.17), dehydrogenation to the 3-oxoacyl intermediate catalyzed by 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35), and oxidative cleavage with loss of acetyl-CoA catalyzed by 3-oxoacyl-CoA thiolase (EC 2.3.1.16). The resulting 10-phenyldecanoyl-CoA (C104.358-CoA) can be hydrolyzed by fatty acyl-CoA hydrolase (EC 3.1.2.2; see Fig. 4.83) to 10-phenyldecanoic acid (C10-4.358). In addition, it is substrate of a subsequent cycle of b-oxidation to 8-phenyloctanoic acid, and further on all the way to 2-phenylacetic acid. See also Fig. 4.85 in which the b-oxidation to 4-phenylbutanoic acid (4.320) was alluded to.
2263
Fig. 4.93. A more complex case of b-oxidation is presented by the thromboxane A2 receptor antagonist known as ()-S-145 (4.359) [246]. When incubated in rat hepatocytes and rat liver peroxisomes, its fatty-acyl side chain indeed underwent boxidation. Interestingly, two independent pathways of b-oxidation were characterized due to the presence of the (Z)-configured CC bond at the 5-position of the side chain. In the first pathway, this CC bond was reduced by an NADPH-dependent reductase to yield 4.360 before b-oxidation produced the C2-shortened metabolite 4.361. In the second pathway, the parent compound was substrate of a first cycle of b-oxidation to yield the C2-shortened metabolite 4.362. Further b-oxidation of the latter to produce the C4-shortened metabolite 4.363 first necessitated reduction (or perhaps 3 ! 2 displacement) of the CC bond. A recent example of b-oxidation is provided by [99mTc]tricarbonyl(15-cyclopentadienyl pentadecanoic acid)technetium (4.364; abbreviated as [99mTc]CpTT-PA) [247]. This compound has been developed as a potential diagnostic tool in heart diseases. And, indeed, it was incorporated in rat myocardium, recognized as a fatty acid, and metabolized as such by b-oxidation. The C12-shortened analogue (produced by six cycles of b-oxidation) was the major metabolite found in heart lipids and heart perfusate.
2264
Fig. 4.94. The two previous Figures illustrate the b-oxidation of xenobiotic carboxylic acids. However, these are not the only cases of interest here, since w-oxidation of an alkyl side chain in a xenobiotic compound may also yield a metabolite able to undergo b-oxidation. This situation is exemplified here with 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (4.365; CI-976), a highly effective inhibitor of cholesterol Oacyltransferase (EC 2.3.1.26; ACAT) with potential as an inhibitor of cholesterol absorption and deposition [248]. When incubated with liver microsomes from humans or animals, the compound was oxidized at various positions in its alkyl side chain, yielding ketones and the carboxylic acid metabolite 4.366. In rats in vivo and in vitro, the latter metabolite underwent three cycles of b-oxidation to produce the C6shortened carboxylic acid 4.367. In addition, a C5-shortened homologue was produced as a minor metabolite, but it was not seen upon incubations of 4.366 or its w-OH precursor. This intriguing metabolite further illustrates the complexity of the endogenous metabolic pathways which xenobiotic carboxylic acids may enter. A somewhat different picture emerges with the statins, two of which are used in their lactone, prodrug form, namely lovastatin and simvastatin (4.181; see Fig. 4.53), while most others are used as the active hydroxy acids. Several statins including simvastatin and lovastatin have been shown to undergo one or two cycles of b-oxidation [249], and indeed their hydroxy-acid form is known to yield an acyl-CoA thioester. However, the (R)-configured 3-OH group in statins prevents b-oxidation (see Fig. 4.92); an inversion of configuration is necessary and occurs via dehydration at C(2) and C(3), as shown here.
2265
Fig. 4.95. The chain elongation by C2 units is known for a small number of substrates [204]. An example is that of benzoic acid (4.314) which in the horse yielded small amounts of 3-hydroxyphenylpropionic acid (4.370) and possibly also 3-oxo-3-phenylpropanoic acid (4.369) [250]. These metabolites were also produced from exogenous (radiolabeled) benzoic acid, and they represented stable intermediates in a cycle of C2 addition. Even more informative is the case of 5-(3-carboxypropyl)picolinic acid (4.372). This metabolite was formed in rats by the oxidative dechlorination of the dopamine b-hydroxylase inhibitor 5-(4-chlorobutyl)picolinic acid (4.371), and it was excreted mainly as the C2-elongated metabolites 4.373 to 4.376 [204] [251]. The four metabolites are arranged here in a biochemically logical sequence allowing comparison with b-oxidation (Fig. 4.92). This reveals the remarkable fact that several enzymes in b-oxidation also catalyze the reverse reaction. Indeed, acetyl-CoA transfer to the CoAconjugate of 4.372 to produce 4.373 was most likely catalyzed by EC 2.3.1.16 (here known as acetyl-CoA C-acyltransferase). Reduction of 4.373 to 4.374 is catalyzed by EC 1.1.1.35 acting as a hydrogenase, while dehydration of 4.374 to 4.375 is expected to be catalyzed by EC 4.2.1.17 acting as a dehydrase. The last step is a hydrogenation catalyzed by the NADPH-dependent trans-2-enoyl-CoA reductase (EC 1.3.1.38), an enzyme distinct from the flavoprotein acyl-CoA oxidase (EC 1.3.3.6) which initiates boxidation. Note that the elongation of 4.372 was also seen in other animal species including humans. Also worthy of note is the fact that all known reactions of chain elongation involve a single C2 unit, except for cyclopropanecarboxylic acid (4.356) which was elongated up to C16 depending on animal species [204].
2266
Fig. 4.96. An intriguing metabolic reaction has attracted much interest since the 1970s, namely the inversion of sense of chirality of non-steroidal anti-inflammatory 2arylpropanoic acids (i.e., profens), the most investigated of which is ibuprofen (4.332), an extensively used drug [252] [253]. It took many years and a number of research teams to characterize the enzymology and mechanism of the reaction, which are now fairly well understood. As shown here, the first step is the formation of an acyl-CoA intermediate, a reaction catalyzed by long-chain acyl-CoA ligase (EC 6.2.1.3; Fig. 4.82) [206] [254]. This reaction is enantioselective in that it shows a marked or practically exclusive preference (depending on animal species) for the inactive ()-(R)-profens [255]. In other words and in the case of ibuprofen, the ligase forms only or mainly the (R)-ibuprofenoyl-CoA. Once formed, this intermediate is the substrate of a reaction under inversion of configuration catalyzed by 2-methylacyl-CoA 2-epimerase (EC 5.1.99.4; a-methylacyl-CoA racemase; human gene AMACT), a peroxisomal and mitochondrial enzyme catalyzing an essential step in the oxidation of cholesterol to cholic acid [256] [257]. This reaction is one of racemization when considering only the substrate moiety, but, in strictly correct terms, it is one of epimerization, since the acylCoA conjugate contains several stereogenic centers (see Fig. 4.71). As a result of epimerization, the ibuprofenoyl moiety now exists in the (R)- and (S)-forms, and acylCoA thioesterases act on both (R)-ibuprofenoyl-CoA and (S)-ibuprofenoyl-CoA to liberate the corresponding ibuprofen enantiomer. In the metabolic scheme shown here, (S)-ibuprofen is thus an end-point only, not an entry point; in contrast, (R)-ibuprofen is both.
2267
Fig. 4.97. A few profens beside ibuprofen have been shown to undergo inversion of configuration in humans, namely ketoprofen (4.377), fenoprofen, and benoxaprofen [258] [259]. In vivo and in vitro results in a variety of animal species indicate that the extent of inversion of profen depends strongly on substrate as well as on species [252] [260]. Furthermore, inversion of configuration is not restricted to 2-methylsubstituted arylacetic acids, witness KE-748 (4.378), the active metabolite of the antirheumatic agent KE-298 [261]. Like ibuprofen, KE-748 underwent extensive (R)to-(S) inversion when administered to rats or incubated with rat hepatocytes. An apparently unconnected example is that of phytanic acid (4.379), namely (3RS,7R,11R)-3,7,11,15-tetramethylhexadecanoic acid. This branched fatty acid is present in various dietary sources, in particular in the fat of ruminant animals where it accumulates as a metabolite of phytol, itself a decomposition product of chlorophyll. In humans and animals, phytanic acid is conjugated to coenzyme A, but its 3-methyl substitution forbids subsequent b-oxidation [244]. Instead, the phytanoyl-CoA intermediate is substrate of a-oxidation to form the coenzyme A conjugate of pristanic acid, more accurately the two epimers (2S)- and (2R)-pristanoyl-CoA (4.380). bOxidation to form propanoyl-CoA is now possible, but only for (2S)-pristanoyl-CoA; 2-methylacyl-CoA 2-epimerase is necessary to catalyze the inversion of configuration of (2R)-pristanoyl-CoA and avoid accumulation of (2R)-pristanic acid [256] [257] [262]. To us, phytanic acid (4.379) thus appears as an example at the interface of xenobiotics and alimentary compounds.
2268
Fig. 4.98. This Figure opens an important Chapter dedicated to glutathione (4.385; GSH), a tripeptide playing an essential role in the protection of organisms against a variety of environmental insults. We initiate this Chapter with the biosynthesis of glutathione (4.385) as schematized in the left part of the Figure [263] [264]. The reaction begins with the formation of g-glutamyl-cysteine (4.383) from l-cysteine (4.381) and l-glutamic acid (4.382), as catalyzed by g-glutamylcysteine synthetase (EC 6.3.2.2). Glycine (4.384) is introduced in the second step catalyzed by glutathione synthetase (EC 6.3.2.3); both reactions are ATP-dependent. The all-important and limiting component of GSH is cysteine, whose SH group is responsible for its conjugating and antioxidant capacities. Indeed, glutathione is not only an important conjugating compound, it is also an essential antioxidant agent, so essential that its physiological concentrations in cells and plasma are in the 0.5 10 mm and micromolar range, respectively [265]. In the body, GSH exists in a redox equilibrium with an oxidized form known as glutathione disulfide (GSSG) [266]. Glutathione acts mainly as a radical scavenger as summarized in the right side of the Figure [267 269]. Like other endogenous thiols including serum albumin, glutathione scavenges free radicals, in particular C-centered radicals (Reaction 1) and reactive oxygen species (ROSs) such as the HO . radical, superoxide, and peroxide radicals (Reactions 2 5). These reactions transform GSH into the glutathionyl radical (GS . ) which is detoxified by reacting with a second GS . radical to yield GSSG (Reaction 6). The latter is recycled to GSH by glutathione disulfide reductase (EC 1.8.1.7; Reaction 7) [263] [264]. As such, GSH plays a critical role in cellular protection against oxidative stress and radiations [270].
2269
Figs. 4.99 and 4.100. Whatever the significance of radical scavenging reactions in the cellular protection, our scope remains on xenobiotic metabolism, and specifically here on GSH-dependent conjugations. These are catalyzed by glutathione S-transferases (EC 2.5.1.18; GSTs), a large and diverse group of enzymes present in the cytoplasm, in the endoplasmic reticulum, in mitochondria, and in peroxisomes [10] [271 274]. Not one but two superfamilies of genes exist in animals, namely those coding for the cytoplasmic superfamily of enzymes (GSTs in the narrow sense), and those coding for the microsomal superfamily of enzymes (designated as MGSTs when distinguished from the cytoplasmic GSTs). In humans, the microsomal enzymes are the products of three MGST genes, and they function as homotrimers. The cytoplasmic (i.e., soluble) enzymes are products of the GST genes, a large number of which are known. These enzymes function as homodimers or heterodimers as shown. The main functions of these enzymes are the formation of conjugates of endogenous and exogenous compounds, and these are the relevant functions we will present here. In addition, these enzymes perform other physiological functions such as isomerization, reduction, thiolysis, and transport which fall outside our scope.
2270
Fig. 4.100.
2271
Figs. 4.101 4.103. Fig. 4.101 focuses on some common features in the catalytic mechanism of glutathione S-transferases [275] [276]. A main element in this mechanism is the acidity of the SH group in glutathione, which in aqueous solution has a pKa of 9.0 and is thus poorly ionized at physiological pH. Significantly, SH acidity is markedly increased (pKa in the range 6 7) when GSH is bound to glutathione Stransferases [277]. This 100- to 1000-fold increase in acidity results from a considerable stabilization of the ionized thiol, a stabilization achieved in particular by an H-bond donation from a neighboring tyrosine residue. This increased acidity is translated into an increased nucleophilicity toward reactive electrophiles, and the thiolate anion in GS is thus the catalytically active group in GST-bound glutathione. In turn, the reactivity of the substrate is increased by polarization of its electrophilic center, as shown in Fig. 4.101 for 4-phenylbut-3-en-2-one (Panel a). This Panel shows the initial catalytic step in reactions of glutathione addition, whose main types of substrates and products are reviewed in Fig. 4.102. Panel b in Fig. 4.101 schematizes the transition state in a reaction of glutathione addition elimination whose substrate here is 1-chloro-2,4dinitrobenzene. The main types of substrates and products of these reactions are reviewed in Fig. 4.103. Both Panels a and b are highly simplified representations (modified from [275a]) which do not incorporate further residues involved in catalysis and/or substrate binding by hydrophobic and electrostatic interactions [278]. Furthermore, the high structural flexibility of glutathione S-transferases (GSTs) is not taken into account here [279].
2272
Fig. 4.102.
Fig. 4.103.
2273
Fig. 4.104. An intriguing aspect of glutathione conjugation is the potential occurrence of nonenzymatic reactions [280]. In an enlightening and still current review, Ketterer has highlighted the role of nonenzymatic glutathione conjugation reactions in xenobiotic metabolism, offering a cogent classification into four possible scenarios [280a]. Thus, a given chemical containing a potential target group may be a good or a poor substrate of glutathione transferases; it may also be able or unable to react spontaneously (i.e., nonenzymatically) with glutathione in solution. The four resulting combinations are shown here; the first two cases involve reactions which, in vitro and in vivo, will be mediated mainly (Case 1) or solely (Case 2) by GSTs. Case 3 involves mainly or exclusively nonenzymatic reactions, whereas Case 4 comprises chemicals resistant to GSH conjugation. The remainder of the Figure compares the nonenzymatic vs. enzymatic GSH conjugation of five xenobiotics; the reactions were monitored spectrophotometrically and involved a 1-min incubation of the xenobiotic with GSH in the absence of enzymes, followed by the addition of an aliquot of rat liver cytosol and a further 1-min incubation [280a]. 4-Nitrobenzyl chloride (4.386) and 1-chloro-2,4dinitrobenzene (4.387) are seen to be good GST substrates and to react spontaneously with GSH. 1,2-Dichloro-4-nitrobenzene (4.388) was a fair GST substrate and reacted spontaneously with GSH. 1-(4-Nitrophenoxy)propane 2,3-oxide (4.389) was a poor GST substrate but reacted spontaneously with GSH, whereas (E)-4-phenylbut-3-en-2one (4.390) was almost inert.
2274
Fig. 4.105. A convenient mechanism accounting for the nonenzymatic reactions of glutathione is based on electrophilicity nucleophilicity considerations [281]. Indeed, electrophiles and nucleophiles are ranked according to their softness or hardness. Thus, hard electrophilic sites have a highly localized positive charge (i.e., a high charge density) which is poorly polarizable (i.e., remains highly localized during the approach of the reaction partner). In contrast, soft electrophilic sites have a delocalized positive charge (i.e., a low charge density) which is readily polarizable by the approaching reaction partner. For the definition of hard and soft nucleophilic sites, the reader just needs to replace electrophilic with nucleophilic and positive with negative in the two previous sentences. Glutathione (in protonated and ionized form) is a soft nucleophile, and as such will react relatively easily with soft electrophiles; this spontaneous reactivity will allow a small (Case 1 in Fig. 4.104) or large (Case 3 in Fig. 4.104) percent of the conjugate to be formed nonenzymatically, depending on enzymatic efficiency. In the presence of hard electrophiles, spontaneous reaction is precluded (Cases 2 and 4 in Fig. 4.104).
2275
Fig. 4.106. Glutathione and glutathione transferases have evolved as a major (in fact, THE major) chemical protection against reactive xenobiotics and reactive compounds produced during the metabolism of endogenous and exogenous compounds. Examples include products of lipid peroxidation and radiation damage (see also Fig. 4.98) [282] [283]. The Table shown in this Figure (taken from [281a]) points to the fact that thiols are among the softest endogenous nucleophiles, implying that GSH will react preferentially with the soft electrophiles on the right of the Table. Were it not for catalytic facilitation by GSTs, GSH would not be able to detoxify the harder electrophiles listed here. Significantly, these harder electrophiles are precisely the ones that best react spontaneously with various nucleophilic sites in nucleic acids, being thus able to induce DNA damage. Because things are never simple in nature, the neat detoxification mechanisms of GSH-GSTs may sometimes backfire and yield reactive metabolites [284]. This will be illustrated in some of the following Figures.
2276
Fig. 4.107. Once formed, glutathione conjugates 4.391 are extensively processed in the body through transport and degradation. Thus, they are substrates of a number of transporters (carriers and export pumps) which mediate their transport across cell membranes in liver, intestine, and kidney, among others organs [285] [286]. More significant in our context is their stepwise enzymatic breakdown to their major excretion products. Their degradation begins with the cleavage of the glutamyl residue by g-glutamyltranspeptidase (EC 2.3.2.2; human genes GGT1, GGT3, GGT5, and GGT6). These are membranal enzymes present in the liver, kidneys, and other organs. The resulting cysteinylglycine conjugate 4.392 loses its glycyl moiety by the action of various dipeptidases (EC 3.4.13). The cysteine conjugate 4.393 so produced undergoes a reaction of N-acetylation catalyzed by cysteine S-conjugate N-acetyltransferase (EC 2.3.1.80), a microsomal enzyme found mainly in the kidney. The product is an Nacetylcysteine conjugate known as a mercapturic acid (4.394), a major urinary excretion product of glutathione conjugates. The N-acetylation of cysteine conjugates is reversible due to the involvement of various amidases (EC 3.5.1). More importantly, both the cysteine and the N-acetylcysteine conjugates are substrates of cysteine Sconjugate b-lyase (EC 4.4.1.13; human genes CCBL1 and CCBL2), a mainly renal and hepatic enzyme which cleaves the SC bond in the cysteinyl moiety, thus liberating a thiolated metabolite, 4.395, of the parent xenobiotic [8] [287 290]. The latter can be further S-methylated by thiol S-methyltransferase (EC 2.1.1.9; TMT; see Chapt. 4.2) to form 4.396. Both 4.395 and 4.396 are substrates of cytochromes P450 and flavincontaining monooxygenases which catalyze their S-oxygenation (see Part 2 [2] [4] [291]).
2277
Fig. 4.108. With this Figure, we begin our survey of the various types of substrates and reactions involved in glutathione conjugation. The Sect. 4.7.2 is dedicated to reactions of additions as summarized in Fig. 4.102, whereas reactions of addition elimination (summarized in Fig. 4.103) will be presented in Sect. 4.7.3. A first class of reactions of addition are on saturated C-atoms, the substrates being the so-called nitrogen mustards (this Figure) and epoxides (Figs. 4.109 4.111). Nitrogen mustards are antitumor alkylating agents containing a (2-chloroethyl)amino function, as exemplified here with mechlorethamine (4.397) [292] [293]. Other drugs include chlorambucil, melphalan, cyclophosphamide, and ifosfamide. The global reaction of conjugation may appear as the substitution of a Cl-atom with a glutathionyl moiety, but its mechanism is not a genuine substitution, since spontaneous dechlorination first forms an aziridinium ion, 4.398, which is the actual alkylating species. This reactive intermediate also undergoes enzymatic and nonenzymatic conjugation with GSH, yielding first the conjugate 4.399, then the diconjugate 4.403 from aziridinium 4.401. Some spontaneous hydrolytic dechlorination also occurs to produce the (2-hydroxyethyl)amino derivatives 4.400, 4.404, and 4.405.
2278
Fig. 4.109. Epoxides are conveniently classified into the reactive arene oxides and the more stable alkene oxides (see Parts 2 and 3 [2 4]). Numerous drugs and other xenobiotics contain a phenyl moiety whose oxidation yields an arene oxide of generic structure 4.406. Nucleophilic attack by the glutathionyl anion at either of the two oxirane C-atoms occurs with inversion of configuration (i.e., an SN2 mechanism) to yield the glutathionyl conjugate 4.407. In vivo, the latter is processed as presented in Fig. 4.107 to yield the N-acetylcysteinyl conjugate, 4.408, known as a premercapturic acid. Compared to the general case in Fig. 4.107, an additional step is required to produce a mercapturic acid, 4.409, namely aromatization by dehydration [283] [294]. A more detailed presentation of the stereochemistry of the reaction is exemplified with phenanthrene 9,10-epoxide (4.410) [275a] [295]. This substrate is a symmetric meso(R,S)-compound, but GSH attack on either oxirane C-atom cancels the plane of symmetry and renders the products chiral. Due to inversion of configuration at the Catom undergoing substitution, the two metabolites are the (9R,10S)- and (9S,10R)conjugates, 4.411. The product stereoselectivity of the reaction depends on the glutathione S-transferase involved; thus, rat M1-1 gave an approximately equal mixture of the two products, whereas rat M2-2 was essentially stereospecific for the (9R,10S)-conjugate [275a].
2279
Fig. 4.110. The glutathione conjugation of alkene oxides is illustrated here with two industrial examples, namely butadiene and styrene. Both xenobiotics are oxygenated by CYP2E1 (see Part 2 [2] [4]) to their respective epoxides, namely butadiene monoepoxide and styrene oxide. Buta-1,3-diene monoepoxide (4.412; see also Part 3 [3] [4]) is substrate of a number of metabolic pathways including GSH conjugation [296]. When incubated with human placental GST, the compound underwent GSH attack at both C-atoms of the oxirane ring, namely at C(1) (Reaction a) and at C(2) (Reaction b) [297]. The conjugate 4.414 resulting from the attack at C(2) proved chemically stable. In contrast, a fast equilibrium was found between conjugate 4.413 (resulting from the attack at C(1)) and two thiirane products resulting from an intramolecular rearrangement, namely the thiirane 4.415 and the episulfonium ion 4.416. Buta-1,3-diene monoepoxide is a chiral compound, yet styrene oxide (4.417) appears better suited to discuss product regio- and stereoselective glutathione conjugation [298]. This compound is a metabolite of styrene, a potential carcinogen. When incubated with liver cytosol from Wistar rats, pure (R)-4.417 gave (S)-4.418 and (R)-4.419 in a 6 : 1 ratio, whereas pure (S)-4.417 gave (R)-4.418 and (S)-4.419 in a 1 : 32 ratio. In other words, the (R)-enantiomer was conjugated preferentially at C(1), whereas the (S)-enantiomer was conjugated almost exclusively at C(2). Results with Sprague Dawley rat liver cytosol were different, since both styrene oxide enantiomers were conjugated predominantly at C(1). Substrate enantioselectivity was also observed in that (R)-styrene oxide was conjugated ca. twice as fast as (S)-styrene oxide. This observation was confirmed with rat purified glutathione S-transferases M, especially M3-3.
2280
Fig. 4.111. Two medicinally relevant examples are shown here, one dealing with the GSH conjugation of an arene oxide, the other with that of an alkene oxide. The in vivo metabolism of the COX-2 inhibitor valdecoxib (4.420) was examined in great details in mice, revealing a total of 16 metabolites which accounted for practically the totality of its in vivo metabolism [299]. Of relevance here was the methyl sulfone 4.422 whose formation was quite reasonably postulated to have involved phenyl epoxidation, glutathione conjugation to 4.421, and finally the various metabolic steps summarized in Fig. 4.107. Another example is simvastatin (4.181) whose glutathione conjugate 4.424 was characterized as a major biliary metabolite in rats administered the drug [300]. This conjugate was most probably formed from the 4a,5-epoxy-6-hydroxy intermediate 4.423.
2281
Fig. 4.112. Polarized alkenyl moieties make good targets for enzymatic and nonenzymatic GSH conjugation by a Michael reaction. The initial catalytic step in reaction has been summarized in Fig. 4.101 using 4-phenylbut-3-en-2-one (4.425), an a,bunsaturated ketone, as an example. Returning to the same substrate, we note that the reaction is regioselective for the C(b)-atom. Furthermore, the substrate has two enantiotopic faces such that the saturation of and addition to the C(b)-atom creates a stereogenic center. Class mu enzymes appear particularly effective in catalyzing the GSH conjugation of phenylbutenone, with the preferential stereoisomer formed being (R)-4.426 [301]. An important feature of the GSH conjugation of polarized alkenes is its reversible nature, the reverse reaction (elimination) being also catalyzed by mu class GSTs. However, and as a rule, this reversibility is modest and its in vivo relevance small compared with that of the glutathione conjugates of isocyanates and isothiocyanates, as we shall see later [302]. The lower part of the Figure presents a selection of polarized alkenyl moieties known to undergo glutathione conjugation [303]. Shown here are three types of a,b-unsaturated aldehydes, two types of a,b-unsaturated ketones, a,bunsaturated esters, a,b-unsaturated amides, a,b-unsaturated nitriles, and alkenyl groups polarized by two different aryl moieties. Some of these moieties are exemplified in the next two Figures.
2282
Fig. 4.113. Many different classes of chemicals are detoxified by GSH conjugation; for example, toxic endogenous products of radical reactions and lipid peroxidation such as N-propenal purines and pyrimidines, and 4-hydroxyalkenals [303a]. Here, we focus on xenobiotic toxins, namely the two important industrial chemicals acrylamide (4.427) and acrylonitrile (4.431) [304]. Rats administered the two xenobiotics together excreted three mercapturic acids as major urinary metabolites of each chemical. Both acrylamide and acrylonitrile underwent direct glutathione conjugation which resulted in the excretion of the mercapturates 4.428 and 4.432, respectively. Furthermore, they both formed the corresponding epoxide. In the case of acrylamide (4.427), its epoxide formed the two mercapturic acids 4.429 and 4.430 which resulted from GSH addition to the C(a)- and C(b)-atom, respectively. In the case of the epoxide of acrylonitrile, the same two positions were targets of GSH conjugation, with the attack at C(a) producing the mercapturate 4.433. As for the conjugate produced by the attack at C(b), it underwent spontaneous decyanylation before being transformed into the mercapturate 4.434. For both epoxides, C(b)-conjugation predominated over C(a)-conjugation.
2283
Fig. 4.114. A few examples of medicinal relevance are presented here, the broken arrows pointing to the C-atom attacked by GSH. We begin with morphinone (4.435), a rather unstable metabolite of morphine produced by dehydrogenation of its secondary alcohol group [305]. Morphinone was suspected of being responsible for the rapid, dose-dependent decrease in hepatic glutathione content caused by morphine. The hypothesis gained likelihood when the glutathione conjugate of morphinone was unambiguously identified as a biliary metabolite of morphine in guinea pigs, accounting for almost 10% of a dose. The glutathione conjugate of the diuretic drug ethacrynic acid (4.436), a well-known metabolite, is formed both enzymatically and nonenzymatically by attack at the electron-deficient exo-methylidene C-atom [306]. A more intriguing example is that of verlukast (4.437), a leukotriene D4 antagonist that was under development for the treatment of bronchial asthma [307]. The compound is of interest, because it lacks a polarizing carbonyl group, this role being played here by the quinolin-2-yl moiety. Although there was spontaneous GSH addition to verlukast (4.437), the reaction was clearly enzyme-catalyzed in rat liver and renal cytosol. In rats in vivo, the biliary excretion of the glutathione conjugate and its breakdown products accounted for ca. 25% of a dose. Our last example is quite unusual, namely the glutathione-dependent activation of potential prodrugs of cytotoxic thiopurines. Thus, trans-6-[2-acetylethenyl)sulfanyl]guanine (4.438) features a butenone promoiety as target for GSH conjugation [308]. The transient conjugate 4.439 spontaneously eliminated 6-thioguanine (4.440). GST M1-1 and A4-4 were the most active enzymes among the 13 human GSTs examined.
2284
Fig. 4.115. The formation and reactivity of quinones has been discussed repeatedly in Part 2, where their glutathione conjugation was alluded to. We now take a closer look at this reaction, which also proceeds by a mechanism of Michael addition. In biology, quinones play important roles in electron transfer and oxygen activation [309]. They are also significant in a toxicological perspective, as the oxidation of some drugs produces quinones or quinone-imines which may form adducts with biomacromolecules (toxification). This capacity for adduct formation is correlated with their reactivity toward glutathione (detoxification) [283a]. We begin here with natural catechols such as dihydrocaffeic acid (4.441). Oxidation by cytochrome P450 and/or peroxidases yielded the highly reactive ortho-quinone 4.442 which readily formed the three GSH conjugates 4.443, 4.444, and 4.445, the former seemingly being the predominant one [310]. A comparable activation to an ortho-quinone appears to be involved in the neurotoxicity of (methylenedioxy)amphetamine and the infamous ecstasy [311]. An example of a para-quinone is provided by the antioxidant 2-(tertbutyl)hydroquinone (4.446; TBHQ) [312]. At high doses, this compound has been shown to promote kidney and bladder carcinogenicity in the rat. When administered to rats, the compound was metabolized to three biliary glutathione conjugates. These are, in increasing quantitative importance, the two monoconjugates formed from the quinone 4.447, namely 6-glutathionyl-TBHQ (4.448) and 5-glutathionyl-TBHQ, and the diconjugate 3,6-diglutathionyl-TBHQ (4.450). The latter diconjugate proves that the monoconjugate 4.448 is itself a substrate for oxidation conjugation involving the intermediacy of the glutathionyl-quinone 4.449. This further sequence of oxidation is particularly significant in a toxicological perspective, since it often follows transport of the monoconjugate to target tissues [313].
2285
Fig. 4.116. The classical example of a quinoneimine undergoing glutathione conjugation is that of N-acetyl-para-quinoneimine (4.451; see Part 2 [2] [4]), the toxic metabolite of paracetamol (4.142; see Fig. 4.43). The GSH conjugation of this highly reactive electrophile to form the conjugate 4.452 proceeds both enzymatically and nonenzymatically, and it is in direct competition with covalent binding to proteins [280a]. A more recent finding is that of the toxification of tolcapone (4.453), an inhibitor of catechol O-methyltransferase (COMT) whose therapeutic use is known to be associated with a risk of liver disorders. A potential pathway of toxification has emerged with the discovery of the primary amine 4.454 as a reduced metabolite of tolcapone [314]. Indeed, this aromatic amine was readily oxidized by peroxidases, human liver microsomes, or various CYPs to an intermediate that reacted with glutathione to yield the GSH conjugate 4.456. All evidence points to the orthoquinoneimine 4.455 as the reactive species. A comparable story is seen with the antihelminthic drug thiabendazole, whose use is also associated with a risk of nephroand hepatotoxicity. In fact, this risk appears related to the formation of the major metabolite 5-hydroxythiabendazole (4.457) and to subsequent covalent binding to biomacromolecules. Microsomal incubations of thiabendazole or its 5-OH metabolite in the presence of GSH afforded the glutathione conjugate 4.459 whose formation was consistent with the intermediate quinoneimine 4.458 [315]. The structure of this intermediate is interesting in that the imino moiety is endocyclic, a feature shared by other reactive intermediates [283a].
2286
Fig. 4.117. Of further biological and toxicological interest is the oxidation of some 4alkylphenols (or cyclic systems containing a 4-methylidenephenol moiety) to quinone methides. These metabolites are strong alkylating agents which undergo Michael additions, thereby binding covalently to soluble and macromolecular nucleophiles [316]. Like other quinones, these quinonemethides are detoxified by glutathione addition, which occurs at the exocyclic methylidene C-atom in 4-alkylphenols, but may occur at other activated positions in more complex systems. Eugenol (4.460), a main component of oil of clove and an antibacterial agent, was oxidized by rat liver and lung microsomes to the quinonemethide 4.461 which reacted nonenzymatically with glutathione [317]. The GSH conjugate 4.462 resulted from addition at the exocyclic CH C-atom, whereas the conjugate 4.463 had undergone addition at the terminal, conjugated CH2 C-atom. A more complex example is provided by the flavonoid quercetin (4.464), which in the presence of peroxidases is oxidized to a quinonemethide existing as three resonance forms which all react with glutathione. The highly delocalized resonance form 4.465 is the one predominating at neutral pH where quercetin exists as an anion. This resonance form features two quinonemethide motifs as shown, but glutathione addition occurs only at ring A to yield the two conjugates 4.466 and 4.467 [318].
2287
Fig. 4.118. In Fig. 4.33, we saw how the sulfate of N-(9H-fluoren-2-yl)-N-hydroxyacetamide (4.110) can undergo heterolytic cleavage to generate a highly reactive, adductforming nitrenium ion. This story was left unfinished and continues here in the context of detoxification by glutathione conjugation. As shown, the nitrenium ion (4.468) exists in a number of resonance forms, implying its stabilization by extended delocalization of its positive charge. Interestingly, these resonance forms can help explain the nonenzymatic production of several glutathione conjugates observed when 4.468 was reacted with glutathione [319]. The formation of four conjugates (4.469, 4.470, 4.471, and 4.472) can be understood as resulting from a direct nucleophilic attack on the electron-poor sites N, C(1), C(3), and C(7). The case of the 4-glutathionyl conjugate 4.474 is of particular interest, since its formation was shown to be an indirect one, the first step being a nucleophilic addition of the HO anion to C(4a) to yield the quinolimide 4.473. The presence of the 4a-OH group enhances the electrophilicity of C(4) and explains the regioselective addition of GSH; a final step of dehydration is needed to restore aromaticity and yield 4.474. An important point to note is that the Nglutathionyl conjugate 4.469 was not isolated as such, but underwent GSH-dependent reduction as discussed in Sect. 4.7.4.
2288
Fig. 4.119. Haloalkenes are important substrates of glutathione transferases, their conjugation with glutathione involving a mechanism known as nucleophilic vinylic substitution (the SNV reaction) [320 322]. These are reactions of addition elimination which we will discuss in Sect. 4.7.3. However, a small sub-group of haloalkenes, i.e., 1,1difluoroalkenes, tends to react by glutathione addition rather than by addition elimination. This is exemplified here with tetrafluoroethene (4.475; tetrafluoroethylene), 1-chloro-1,2,2-trifluoroethene (4.477), and 1-bromo-1-chloro-2,2-difluoroethene (4.479). Their glutathione conjugates (4.476, 4.478, and 4.480, resp.) result from a reaction of addition which is not followed by elimination. An example of some medicinal interest is provided by 1,1,3,3,3-pentafluoro-2-(fluoromethoxy)prop-1-ene (4.482), a potentially toxic breakdown product of the general anesthetic sevoflurane (4.481) generated by CO2 absorbents in anesthesia machines. This breakdown product is a substrate of GSH conjugation; as a 1,1-difluoroethene derivative, it does yield the addition conjugate 4.483 [323]. And, in analogy with most haloalkenes, it also yields the product of addition elimination 4.484. The major toxicological interest of both glutathione conjugates is their further biotransformation to reactive metabolites identified or inferred in patients and in rats. Indeed, the two glutathione conjugates are transformed to cysteine conjugates and mercapturic acids which, in turn, undergo blyase-catalyzed cleavage to the thiols 4.485 and 4.486 (see Fig. 4.107). These thiols spontaneously rearrange by loss of HF (in case of 4.485) or tautomerism (in case of 4.486) to yield the highly reactive thioacyl fluoride 4.487. The latter can bind covalently to biomacromolecules, thus accounting for the nephrotoxicity of compound 4.482, or react with H2O.
2289
Fig. 4.120. A few alkynes (i.e., acetylenic derivatives) are known to undergo glutathione conjugation; these substrates have in common a CC bond activated by electron delocalization. A simple example is provided by dichloroethyne (4.487; dichloroacetylene), a product of the alkaline decomposition of trichloroethylene and a potent neurotoxin and nephrotoxin [324]. In rats exposed to low levels of dichloroethyne vapors, the compound underwent glutathione conjugation as its major metabolic pathway. The glutathione conjugate 4.488 and the mercapturic acid 4.489 were major metabolites in bile and urine, respectively. Other metabolites were breakdown products of the thiol 4.490. High covalent binding was seen to albumin, hemoglobin, renal DNA, and renal proteins, and was caused by reactive species such as the thioacyl chloride 4.491. A medicinal example is that of the antifungal agent terbinafine (4.492). When incubated with human or rat liver microsomes, the drug underwent CYP-catalyzed N-dealkylation to the secondary amine 4.493 and the highly unsaturated aldehyde 4.494 [325]. The latter was trapped by GSH added to the incubates, yielding the glutathione conjugate 4.495 which retains a second reactive electrophilic site. This conjugate has thus been postulated to be excreted in the bile where it could cause hepatobiliary dysfunction.
2290
Fig. 4.121. Organic isocyanates (RN CO) are used extensively to manufacture paints, pesticides, and polyurethanes. Their reactivity can explain toxic reactions, namely a) massive damage to exposed areas (respiratory tract, eyes, etc.) in the case of heavy accidental exposure, as exemplified by the effects of the infamous methyl isocyanate [326]; and b) hypersensitivity of the respiratory tract, as seen in workers exposed to polluted atmospheres. At the molecular level, the toxicity of isocyanates is a consequence of their reactivity as electrophiles toward biomacromolecules such as proteins (Reaction a). Their main pathway of detoxification is by hydrolysis (Reaction b), but the amine so liberated may produce hypersensitivity [107]. Isocyanates also react enzymatically and spontaneously with glutathione, the reaction being reversible. As exemplified here with methyl isocyanate (4.496), its glutathione conjugate 4.497 can liberate the parent compound or be processed to cysteine conjugates (e.g., the mercapturate 4.498) which also liberates 4.496 [327]. Because glutathione conjugates are substrates of various transporters, they may reach deep compartments in the body and, if the conjugation is reversible, liberate therein a toxic isocyanate [328]. In other words, GSH conjugates of isocyanates are transport forms as much as products of detoxification. The lower part of the Figure presents other examples. Thus, 2,4diisocyanatotoluene (4.499) is another chemical widely used in the paint and plastic industries, and a cause of occupational asthma [329]. Isocyanates may also be formed as metabolites of xenobiotics, as exemplified with N-formylamphetamine (4.500), a contaminant in illicit preparations of amphetamine analogues, and the antitumor agent sulofenur (4.502). The former is oxidized by CYPs to the isocyanate 4.501 [330], whereas the latter undergoes general base-catalyzed cleavage to para-chlorophenyl isocyanate (4.503) [331].
2291
Fig. 4.122. A number of edible cruciferous vegetables such as broccoli, cabbage, and cauliflower contain organic isothiocyanates known to induce various glutathione Stransferases. The metabolism of these natural products is of interest due to their chemoprotective properties. One such compound is sulforaphane (4.504), the metabolism of which was carefully investigated in rats [332]. As shown here, sulforaphane (4.504) underwent both redox and conjugation reactions. A major route was sulfoxide reduction to erucin (4.505), whereas a minor pathway was dehydrogenation to 4.506. Three metabolites were identified in the bile, namely the glutathionyl conjugates of erucin and sulforaphane, i.e., 4.507 and 4.508, respectively, and the conjugate 4.509. The mercapturate metabolites of sulforaphane (4.504) and erucin (4.505) were the major urinary metabolites. Other natural isothiocyanates known to undergo enzymatic and nonenzymatic glutathione conjugation are allyl isothiocyanate (4.510), benzyl isothiocyanate (4.511), and phenethyl isothiocyanate (4.512) [333]. Like that of isocyanates, the glutathione conjugation of isothiocyanates is reversible, with the forward reaction being markedly faster than the reverse one. The GSTs A1-1, A2-2, M1a-1a, and P1-1 were shown to be catalytically competent.
2292
Fig. 4.123. This Section presents the major reactions of glutathione conjugation involving nucleophilic substitution, better designated as nucleophilic addition elimination. In a first part, we shall examine conjugation at sp3-C-atoms, and we begin with simple haloalkanes, namely chloroalkanes and bromoalkanes [334]. Their conjugation with glutathione occurs according to an SN2 mechanism, in other words, a nucleophilic substitution with inversion of configuration. This was nicely shown in a number of studies, for example, with the model compound 2-bromo-3-phenylpropanoic acid (4.513) [335]. In the presence of rat liver cytosol, glutathione conjugation was substrate-enantioselective in that the (R)-enantiomer was a better substrate of GSTs than the (S)-enantiomer. The reaction was also product-stereoselective in that the (R)enantiomer was metabolized to the epimeric (S)-4.514 conjugate, whereas the (S)enantiomer gave the (R)-4.514 conjugate. In a toxicological perspective, it is informative to examine the conjugation of dichloromethane (4.515), a compound representative of toxic halomethanes [336] [337]. Nucleophilic substitution of the Clatom yields a conjugate, 4.516, reactive enough to form DNA adducts. This metabolite can undergo nonenzymatic hydrolytic dechlorination to 4.517, itself an unstable metabolite which loses GSH to yield the toxic formaldehyde (4.518). Another reaction worthy of mention is the GSH-dependent reduction of 4.517 to methanol (4.519), a type of reaction to be discussed in Sect. 4.7.4 (see also Fig. 4.118).
2293
Fig. 4.124. Haloalkanes containing a 1,2-dihaloethyl motif are another class of xenobiotics able to undergo GSH/GST-catalyzed toxification [338]. The nematocide 1,2-dibromo-3-chloropropane (4.520) offers an eloquent example of alternating steps of toxification and detoxification characteristic of the metabolism of numerous xenobiotics. The compound is a persistent environmental pollutant that was used as a soil fumigant. Two major metabolic pathways lead to its toxification. The first pathway is a CYP-catalyzed oxidation to 2-bromoacrolein (4.521), followed by GSH conjugation to 4.522, cyclization to the episulfonium species 4.523, hydrolytic ring opening of the three-membered (thiirane) ring to 4.524, and reduction to the diol conjugate 4.525. The second pathway is the direct, GST-catalyzed formation of the glutathione conjugate 4.526 [339]. The latter is unstable by virtue of its vicinal halide-glutathione motif and undergoes spontaneous debromination to form an intermediate episulfonium species, 4.527, able to bind covalently to DNA. This fact is indicated in the Figure by the red boxes in which the episulfonium formulae are embedded. This toxic species can also be detoxified by hydrolytic ring opening to 4.528 and 4.529, or by formation of the diglutathionyl conjugate 4.530. However, two among the three resulting metabolites, i.e., 4.529 and 4.530, retain a vicinal halide-glutathione motif and can, in turn, form an episulfonium ion, 4.531 and 4.532, respectively. These routes are followed by another round of detoxification by hydrolysis or GSH conjugation, yielding metabolites 4.525, 4.533, and 4.534, respectively.
2294
Fig. 4.125. Halide atoms in haloalkanes are electron-withdrawing substituents which activate (render electrophilic) these compounds toward GSH conjugation. The same mechanism was presented in Figs. 4.30 4.32 (Chapt. 4.3), where we saw how reactive arylmethanol sulfates are detoxified by glutathione conjugation. The benzylic C-atom in arylmethanol sulfates is strongly activated by the electron-withdrawing O-sulfate moiety. Besides haloalkanes and arylmethanol sulfates, a few other types of substituents facilitate GSH conjugation by addition elimination at sp3-C-atoms, notably sulfoxide and sulfone groups as exemplified here. Diallyl sulfide (4.535), a flavor component of garlic, is considered a chemoprotective agent due to its inhibition of CYP2E1-toxification of some carcinogenic chemicals. Rats dosed with 4.535 excreted in their bile a variety of metabolites resulting from initial sulfoxidation and glutathione conjugation [340]. In vitro, diallyl sulfoxide (4.536) and diallyl sulfone (4.537) reacted spontaneously with glutathione to form the GSH conjugate 4.538. The moieties eliminated, 4.539 and 4.540, respectively, were not characterized as such, but 4.540 formed a glutathionyl disulfide, 4.541, according to a reaction discussed in Fig. 4.130. Our next example is a medicinal one, namely pantoprazole (4.542), an irreversible proton pump inhibitor used to treat peptic ulcers and other related diseases [341]. As shown with Reaction a, the benzylic position is activated by the SO group and is a good target for glutathione conjugation, as seen in rats dosed with the drug. Interestingly, the C(2)-atom of benzimidazole was also found to be a site of GSH addition elimination according to a mechanism discussed below (see Fig. 4.127). Note that neither of the two GSH conjugates 4.543 and 4.544 was identified as such but as further breakdown products.
2295
Fig. 4.126. With the exception of 1,1-difluoroalkenes (see Fig. 4.119), haloalkenes tend to react with GSH/GSTs in a reaction of addition elimination whose mechanism is a nucleophilic vinyl substitution (SNV) [320] [321] [342]. This mechanism involves a reaction intermediate where the target C-atom is in an sp3-configuration, in close analogy with the reaction of aromatic substitution to be presented in the next Figure. Haloalkenes have a number of industrial uses and are also environmental contaminants. They undergo CYP-catalyzed oxidation and GST-catalyzed conjugation, the enzymes in the latter case being mainly microsomal glutathione S-transferases [319]. Haloalkenes of relevance here include the much studied 1,1,2,2-tetrachloroethylene and 1,1,2-trichloroethylene [343] [344]. However, we focus on 1,1,2,3,4,4-hexachlorobuta-1,3-diene (4.545), since it appears to be metabolized in vivo exclusively by glutathione conjugation [320]. As shown, the glutathione conjugate of hexachlorobutadiene, 4.546, is formed at C(1); it is then degraded to the cysteinyl and mercapturate conjugates, 4.547 and 4.548, respectively. The latter is preferentially excreted renally, while the former is a preferred substrate of b-lyase to yield the thiol metabolite 4.549. This thiol has an intrinsic reactivity which favors its isomerization to the thioacyl chloride 4.550, and its loss of HCl to form the thioketene 4.551. Both are highly reactive metabolites which react with nucleic acids and proteins, thereby accounting for the toxicity and carcinogenicity of hexachlorobutadiene and other haloalkenes. However, detoxification of the thioacyl chloride 4.550 and the thioketene 4.551 is also well known, particularly by hydrolysis to the thio O-acid 4.552 (and to the corresponding carboxylic acid).
2296
Fig. 4.127. Addition elimination reactions of glutathione to substituted aromatic rings are comparable to those targeting haloalkenes, except among other things for a greater number of activating and displaceable groups. The mechanism of the reaction, as exemplified here with 1-chloro-2,4-dinitrobenzene (4.553; see also Fig. 4.101) begins with the formation of a s-complex (also known as a Mesenheimer complex) [275a]. The better the delocalization of the negative charge to electron-withdrawing ortho- and para-substituents, the easier is the formation of the complex. The overall rate of formation of the GSH conjugate 4.554 will also depend on the relative ease of elimination of the substituent, the formation of the s-complex being reversible. A number of chloro- and fluoroarenes are known to be substrates of the reaction, for example 1,3,5-trifluoro-2-nitrobenzene (4.555) where any of the three F-atoms can be displaced [345]. A number of human GSTs catalyze the reaction, e.g., A1-1, A2-2, M1a-1a, and P1-1. Other substrates of the reaction include aryl sulfoxides (e.g., 4.556), aryl sulfones, and arylsulfonamides [346]. The GSH conjugation of the antihypertensive agent moxonidine (4.557) may appear unexpected until one realizes that a scomplex at C(4) has its negative charge delocalized to the three neighboring N-atoms [347]. A similar reasoning applies to chlorpyrifos (4.558), a widely used pesticide to which many humans and animals are exposed [348]. This xenobiotic is conjugated by GSTs at C(6) (loss of the Cl anion to yield conjugate 4.559) and C(2) (loss of the diethyl thiophosphate moiety to yield 4.560). In both cases, the geminal N-atom and an ortho-Cl substituent delocalize the negative charge.
2297
Fig. 4.128. A seemingly special case of glutathione conjugation has been reported for remoxipride (4.561) [349]. This atypical neuroleptic was withdrawn in 1993 due to a few cases of aplastic anemia observed in patients receiving the drug. Based on in vitro studies, a potential mechanism of toxification was deduced which implicated a known human metabolite of the drug, namely its hydroquinone derivative 4.562. When incubated with stimulated human neutrophil granulocytes, this metabolite underwent peroxidase-catalyzed oxidation to the reactive quinone 4.563, which reacted with glutathione to form the glutathionyl conjugate 4.564. The formation of this metabolite was demonstrated unambiguously; assuming its formation indeed involved the postulated pathway, it would imply a reaction of addition elimination resembling the GSH conjugation of both haloalkenes and haloarenes. The monoglutathionyl conjugate 4.564 was substrate of a second round of oxidation to 4.565, followed by a GSH Michael addition to the diglutathionyl conjugate 4.566. The latter was oxidized further to a quinone before undergoing cyclization (not shown). In summary, the reactive quinones detected in this study bring convincing evidence for multiple peroxidase-catalyzed toxifications alternating with glutathione conjugations.
2298
Fig. 4.129. Activated derivatives of carboxylic acids can behave as acylating agents toward nucleophiles, and they tend to react enzymatically and/or spontaneously with glutathione. Acyl halides among the most reactive among such derivatives, and particularly acyl chlorides used extensively in organic chemistry. An interesting example of such a compound has been reported as a metabolite of 1,1-dichloroethene (4.567; 1,1-dichloroethylene) [350]. This chemical is extensively used in the manufacture of plastics and is known to be a lung and liver toxicant. Its major route of toxification in human lung and liver microsomes was found to involve CYP2E1 oxidation to the epoxide 4.568, followed by GSH addition and HCl elimination to generate the adduct-forming (S-glutathionyl)acetyl chloride (4.569). The latter reacted (presumably spontaneously) with GSH to form (S-glutathionyl)acetyl glutathione (4.570), and with water to form S-glutathionyl acetate (4.571). Other activated acyl derivatives of distinct relevance in xenobiotic metabolism are acyl glucuronides (see Chapt. 4.4) and acyl-coenzyme A conjugates (see Chapt. 4.6), both being able to form glutathione conjugates in a reaction of transacylation (Figs. 4.50 and 4.83). Thus, the lipid-lowering agent clofibric acid (4.572) forms an acyl-CoA conjugate (4.573) and an acyl glucuronide 4.574, both of which are intermediates in the in vivo and in vitro formation of clofibryl-S-acyl-glutathione 4.575 [351].
2299
Fig. 4.130. Another reaction of GSH conjugation that can formally be considered as an addition elimination is the formation of mixed glutathionyl disulfides. One mechanism for their formation is by reaction of the glutathionyl radical with another thiyl radical, in analogy with the formation of oxidized glutathione (GSSG; see Fig. 4.98). However, this mechanism does not appear to be effective compared to the xenobiotic thiol being oxidized to a sulfenic acid (RSOH) prior to reacting with GSH. A classical example is that of the antimineral corticoid (diuretic) drug spironolactone (4.576). The compound has a complex metabolic fate, a major pathway of which is hydrolysis of the thioacetate ester group to the thiol metabolite 4.577, followed by S-methylation (Chapt. 4.2) to the thiomethyl derivative 4.578, a significant human metabolite. In addition, the thiol 4.577 is oxidized by CYP and/or flavin-containing monooxygenases to the sulfenic acid 4.579 [352]. This reactive metabolite, when leaving the enzyme catalytic site, was trapped by GSH to form the glutathionyl-spironolactone disulfide 4.580 according to the mechanism shown.
2300
Fig. 4.131. A more unexpected example of a mixed glutathionyl disulfide is that of the antidiabetic troglitazone (4.581) whose use has been associated with cases of hepatotoxicity. One pathway in its metabolic fate is scission of the thiazolidinedione ring via an unstable S-oxide (4.582) to form the intermediate sulfenic acid 4.583 [353]. The isocyanate group in the latter is broken down by hydration and loss of CO2 , whereas the sulfenic group accounts for the formation of the glutathionyl disulfide conjugate 4.584. The formation of this metabolite was characterized unambiguously in human liver microsomes containing GSH. Another GSH conjugate (not shown) was the product of addition to the isocyanate group (see Fig. 4.121). Note that this reaction of glutathione with other thiols is not limited to xenobiotics, witness the process of Sglutathionylation [354]. This is a reversible post-translational modification of low-pKa cysteinyl residues in proteins, with pi-class GST catalyzing the forward reaction. The process plays a role in governing how cells respond to oxidative stress. To broaden the perspective further, we note that cysteinyl groups in accessible proteins may also bind some xenobiotic thiols, as exemplified by the well-known angiotensin-converting enzyme inhibitor captopril which, in vivo, forms a disulfide bond with human serum albumin [355].
2301
Fig. 4.132. Glutathione reacts with a number of metallic cations, forming thiolates (previously known as mercaptides) which are thermodynamically stable but kinetically labile. In other words, the formation of thiolates is favored by their low energy, but the equilibrium constant is also markedly dependent on the relative concentrations of the competing thiol ligands. As such, thiolates can serve as transport forms of metals in the organism [356]. Metallic cations forming thiolates include arsenic, cadmium, copper, gold, lead, mercury, platinum, and silver. Three such metals will be exemplified here, namely mercury, arsenic, and platinum. The bond between cationic Hg, As, or Pt and their counterions is more covalent than ionic ( < 30%), explaining why their conjugation with GSH is a reaction of substitution. Cationic Hg is well-known for its strong affinity for thiols, also known as mercaptans. Thus, mercury chloride (4.585) reacts spontaneously with glutathione to form mercurydiglutathione (4.586), whereas methylmercury chloride (4.587) forms methylmercuryglutathione (4.588) [357]. Compound 4.587 also reacts rapidly with Cys-Gly, and the conjugate 4.589 was the main biliary metabolite in rats dosed with 4.587. As for arsenic, it is a worldwide natural contaminant and an occupational hazard (see Figs. 4.20 and 4.21). Like Hg, it has a high affinity for endogenous thiol groups, and is for example highly bound to hemoglobin Cys13a in rats [358]. Arsenic salts react spontaneously with glutathione in solution, as seen with methylarsonite (4.66) which formed the diglutathionyl complex 4.590 [43] [47] [359]. Arsenical drugs used to treat some parasitic infections are also conjugated by GSH. Thus, rats dosed with melarsoprol (4.591) and its analog trimelarsan (4.592) excreted the diglutathionyl conjugate 4.593 in their bile [360].
2302
Fig. 4.133. Platinum complexes have considerable significance in cancer chemotherapy [361]. The kinetics of reaction of PtII complexes with glutathione [362], as well as their hydration [3] [4] play a significant role in their efficacy and toxicity. While a global picture integrating adduct formation with DNA, biotransformation, and the role of transporters is slow to emerge, it appears, for example, that GS platinum complexes may be excreted from cells by efflux pumps. Taking the archetypal drug cisplatin (4.594) as an example, we review here its major glutathione conjugates as formed nonenzymatically in solution under physiological conditions of pH and temperature [363]. At GSH/cisplatin molar ratios equal or larger than 2 : 1, the 2 : 1 complex 4.595 was formed. At a GSH/cisplatin molar ratio of 1 : 1, the 1 : 1 complex 4.596 was formed first, to be progressively replaced by the 1 : 2 GS/Pt complex 4.597. These complexes indicate that the strongest Pt ligand in GSH is indeed its thiol group, followed by an amino and an amido group. The strength of the SH ligand is also obvious in complexes between cisplatin and N-acetylcysteine incubated in a 1 : 1 molar ratio. Here again, a 1 : 1 complex 4.598 was initially formed, to be progressively replaced by a 1 : 2 complex 4.599 having the S-atom bridging two Pt-atoms. The toxicity of the 2 : 1 GS/Pt complex was demonstrated in a cell-free system where it inhibited protein synthesis, and its transport across tumor cell membranes was ATP-dependent. Solutions with a GSH/cisplatin molar ratio of 1 : 1 had a cytotoxicity that increased with increasing concentration of the 1 : 1 complex 4.596, but decreased as the concentration of the 1 : 2 complex 4.597 increased.
2303
Fig. 4.134. In a number of cases, glutathione conjugates react with a molecule of glutathione to yield glutathione disulfide (GSSG) and the reduced substrate. The structural and electronic conditions for such a reaction are schematized in the upper part of the Figure using a generic RYX substrate. First, the group X (often a leaving group) must be a good electroattractor able to activate the target atom Y toward GSH attack. Second, the target atom Y, once coupled to a glutathionyl moiety, must be able to activate the S-atom toward attack by the second glutathione molecule. Heterolytic cleavage of the YS bond yields a molecule of GSSG and the RY anion. Two classes of substrates are exemplified in this Figure, namely a-halo ketones and hydroperoxides. Several 2-chloroacetophenones such as 2,2-dichloroacetophenone (4.600) were investigated as substrates for their GSH-dependent reduction [364]. Glutathione addition and chloride elimination yielded a GS-conjugate (4.601) in which electronic delocalization activated the S-atom. The heterolytic cleavage of the CH2 SG bond allowed reduction of the substrate to 2-chloroacetophenone (4.602). The initial conjugation step was catalyzed by GST O1-1. Our second example is of great physiopathological significance, since it implies the reduction of hydroperoxides 4.603. These compounds are reactive products of lipid peroxidation as well as intermediates in the synthesis of some prostaglandins [152] [365]. Here, GSH attacks the proximal Oatom, but the resulting intermediate 4.604 reacts rapidly with a second glutathione thereby reducing the initial hydroperoxide to an alcohol, 4.605. The first conjugation step was catalyzed by GSTs A1-1, A2-2, and P1-1, whose presence was confirmed in human liver mitochondria [366].
2304
Fig. 4.135. Nitrosoarenes, 4.608, occur as industrial chemicals or as metabolites formed a) by CYP-catalyzed oxidation of aromatic amines, 4.606, to aromatic hydroxylamines, 4.607, followed by autoxidation or peroxidase-catalyzed oxidation, or b) by reductasecatalyzed reduction of nitroarenes [3] [4]. Nitrosoarenes react readily and nonenzymatically with glutathione to form semimercaptals 4.609 [367] [368]. These are metabolic crossroads to three distinct reduction pathways (a, b, and c) whose relative significance depends on experimental conditions (GSH concentration and pH) and substrate properties. Pathway a is a reductive thiolytic cleavage (Fig. 4.134); its product is an N-arylhydroxylamine 4.607. This pathway is favored at relatively high GSH concentrations and for nitrosoarenes with electron-withdrawing substituents. Pathway b is favored by lower pH and relatively low GSH concentrations and for nitrosoarenes with electron-donating groups. It involves an intramolecular, proton-catalyzed rearrangement of the semimercaptal 4.609 to the more stable sulfinanilide 4.610 which tends to undergo proton-catalyzed hydrolysis to the aromatic amine 4.606 and glutathione sulfinic acid. In effect, Pathway b is a reduction of a nitrosoarene to an arylamine. The same is true for Pathway c, which may occur when excess GSH is present. The resulting mercaptal 4.611 then undergoes two GSH-reduction steps producing two GSSG molecules. Our last case is that of AsV salts (see also As methylation under Sect. 4.2.4). They react enzymatically (GST O1-1) and nonenzymatically with glutathione as exemplified here by dimethylarsinic acid (4.67) [47] [48] [359]. The reaction, which is one of addition with elimination of a H2O molecule, yields an intermediate GSH conjugate 4.612 whose reductive thiolytic cleavage (Fig. 4.134) produces the AsIII species dimethylarsinous acid (4.68).
2305
Fig. 4.136. In this last and short Chapter, we examine two unusual types of metabolic reactions, namely the nonenzymatic coupling of xenobiotic amines with endogenous carbonyl compounds [369]. The first type of reaction is covered in the present Figure and involves the condensation of xenobiotic hydrazines and hydrazides with an endogenous ketone or aldehyde to form a Schiff base called a hydrazone. A well-known example is that of the antituberculosis drug isoniazid (4.284), which, besides acetylation (see Chapt. 4.5), forms hydrazones with circulating pyruvic acid and 2oxoglutaric acid to yield the conjugates 4.613 and 4.614, respectively. These are important in vivo metabolites of isoniazid, especially in slow acetylators [191]. A second relevant example is that of hydralazine (4.282), again a substrate of Nacetylation which forms hydrazones. Three such conjugates are formed in humans, namely the acetone hydrazone 4.615, the pyruvic acid hydrazone 4.616, and the 2oxoglutaric acid hydrazone 4.617 [190]. Interestingly, the hydrolysis of the latter two hydrazones in biological media (buffer or plasma) was practically negligible, whereas the former (4.615) did regenerate the parent drug [370]. Hydrolysis was even faster for the acetaldehyde hydrazone, at best a very minor and occasional metabolite.
2306
Fig. 4.137. Bicarbonate ions react with amines to form carbamic acids, a reversible reaction whose rate constants and equilibrium constant depend largely on the reactivity of the amine, on the stability of the carbamic acid, and on external conditions such as pH and concentrations [371]. As shown for 2-haloethylamines such as 2-bromoethylamine (4.618), the reaction involves a nucleophilic attack by the unprotonated amine, meaning that the amine must be basic enough to have a well localized doublet of electrons, yet not too basic for the unprotonated species to be present in sufficient proportion. From the examples in the literature, it appears that a pKa value of ca. 8 is favorable for a reaction under physiological conditions. The carbamic acid thus formed (4.619 in our example) was unstable and easily hydrolyzed back to the free amine. The identification of carbamic acids under physiological conditions is often prevented by this lack of stability. However, the carbamic acid 4.619 reacted intramolecularly to form the stable oxazolidin-2-one 4.620, which served as evidence of the intermediacy of the carbamic acid [372]. A noteworthy number of medicinal amines are known to form carbamic acids in vivo, a reaction greatly facilitated by the high level of endogenous bicarbonate in human blood (around 20 mm). Several of these carbamic acids would rapidly vanish by hydrolysis and remain unidentified, were it not for their capacity to serve as substrates of UDP-glucuronosyltransferases and yield carbonyloxy-b-d-glucuronides [373]. We illustrate this pathway with mexiletine (4.621), an orally effective antiarrhythmic agent [374]. Its carbamic acid derivative 4.622 was not detected, in contrast to its carbamoyl glucuronide 4.623 which was an important urinary metabolite in humans. Three other
2307
medicinal examples (secondary amines, in fact) are shown. Thus, varenicline (4.624) is a partial nicotinic receptor agonist whose carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver preparations [375]. The antimicrobial agent garenoxacin (4.625) was excreted mostly unchanged in experimental animals, with carboxylic glucuronidation and carbamoyl glucuronidation as minor pathways [376]. As for the antidepressant sertraline (4.626), its carbamoyl glucuronide was a major metabolite in dog bile and was also found in the plasma of humans dosed with the drug [377].
REFERENCES [1] B. Testa, S. D. Krmer, The Biochemistry of Drug Metabolism An Introduction. Part 1: Principles and Overview, Chem. Biodivers. 2006, 3, 1053 1101. [2] B. Testa, S. D. Krmer, The Biochemistry of Drug Metabolism An Introduction. Part 2: Redox Reactions and Their Enzymes, Chem. Biodivers. 2007, 4, 257 405. [3] B. Testa, S. D. Krmer, The Biochemistry of Drug Metabolism An Introduction. Part 3: Reactions of Hydrolysis and Their Enzymes, Chem. Biodivers. 2007, 4, 2031 2122. [4] B. Testa, S. D. Krmer, The Biochemistry of Drug Metabolism: Principles, Redox Reactions, Hydrolyses, Verlag Helvetica Chimica Acta, Zurich, and Wiley-VCH, Weinheim, 2008. [5] G. J. Mulder, Ed., Conjugation Reactions in Drug Metabolism, Taylor & Francis, London, 1990. [6] B. Testa, W. Soine, Principles of drug metabolism, in Burgers Medicinal Chemistry and Drug Discovery, 6th edn., Ed. D. J. Abraham, Wiley-Interscience, Hoboken, 2003, Vol. 2, p. 431 498; B. Testa, Principles of drug metabolism 2: Hydrolysis and conjugation reactions, in ADME-Tox Approaches, Eds. B. Testa, H. van de Waterbeemd, Vol. 5 in Comprehensive Medicinal Chemistry, 2nd edn., Eds. J. B. Taylor, D. J. Triggle, Elsevier, Oxford, 2007, p. 133 166. [7] R. A. Totah, A. E. Rettie, Principles of drug metabolism 3: Enzymes and tissues, in ADME-Tox Approaches, Eds. B. Testa, H. van de Waterbeemd, Vol. 5 in Comprehensive Medicinal Chemistry, 2nd edn., Eds. J. B. Taylor, D. J. Triggle, Elsevier, Oxford, 2007, p. 167 191. [8] Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB), Enzyme Nomenclature, www.chem.qmul.ac.uk/iubmb/enzyme; Brenda: The Comprehensive Enzyme Information System, www.brenda-enzymes.info; ExPASy Proteomics Server, www.expasy.org; Enzyme Structure Database, www.ebi.ac.uk/thornton-srv/databases/enzymes; The ESTHER Database, http://bioweb.ensam.inra.fr/ESTHER/definition. [9] J. Caldwell, Conjugation reactions in foreign-compound metabolism: definition, consequences, and species variations, Drug Metab. Rev. 1982, 13, 745 777. [10] D. G. McCarver, R. N. Hines, The ontogeny of human drug-metabolizing enzymes: Phase II conjugation enzymes and regulatory mechanisms, J. Pharmacol. Exp. Ther. 2002, 300, 361 366. [11] E. J. Jeong, X. Liu, J. Chen, M. Hu, Coupling of conjugating enzymes and efflux transporters: Impact on bioavailability and drug interactions, Curr. Drug Metab. 2005, 6, 455 468. [12] a) M. Fujioka, Mammalian small molecule methyltransferases: their structural and functional features, Int. J. Biochem. 1992, 24, 1917 1924; b) L. Yan, D. M. Otterness, T. L. Craddock, R. M. Weinshilboum, Mouse liver nicotinamide N-methyltransferase, Biochem. Pharmacol. 1997, 54, 1139 1149. [13] R. M. Weinshilboum, D. M. Otterness, C. L. Szumlanski, Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase, Annu. Rev. Pharmacol. Toxicol. 1999, 39, 19 52. [14] J. Tenhunen, M. Salminen, K. Lundstrm, T. Kiviluoto, R. Savolainen, I. Ulmanen, Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters, Eur. J. Biochem. 1994, 223, 1049 1059. [15] J. Vidgren, L. A. Svensson, A. Liljas, Crystal structure of catechol O-methyltransferase, Nature 1994, 368, 354 358.
2308
[16] T. Lotta, J. Vidgren, C. Tilgmann, I. Ulmanen, K. Melen, I. Julkunen, J. Taskinen, Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme, Biochemistry 1995, 34, 4202 4210. [17] H. M. Lachman, D. F. Papolos, T. Saiko, Y.-M. Yu, C. L. Szumlanski, R. M. Weinshilboum, Human catechol O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders, Pharmacogenetics 1996, 6, 243 250. [18] a) P. Lautala, I. Ulmanen, J. Taskinen, Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase, Mol. Pharmacol. 2001, 59, 393 402; b) D. R. Thakker, C. Boehlert, K. L. Kirk, R. Antkowiak, C. R. Creveling, Regioselectivity of catechol O-methyltransferase, J. Biol. Chem. 1986, 261, 178 184. [19] K. Johnson, A. Shah, S. Jaw-Tsai, J. Baxter, C. Prakash, Metabolism, pharmacokinetics, and excretion of a highly selective N-methyl-d-aspartate receptor antagonist, traxoprodil, in human cytochrome P450 2D6 extensive and poor metabolizers, Drug Metab. Dispos. 2003, 31, 76 87; C. Prakash, D. Cui, M. J. Potchoiba, T. Butler, Metabolism, distribution and excretion of a selective N-methyl-d-aspartate receptor antagonist, traxoprodil, in rats and dogs, Drug Metab. Dispos. 2007, 35, 1350 1364. [20] R. J. Lantz, T. A. Gillespie, T. J. Rash, F. Kuo, M. Skinner, H. Y. Kuan, P. Knadler, Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects, Drug Metab. Dispos. 2003, 31, 1142 1150. [21] B. T. Zhu, U. K. Patel, M. X. Cai, A. H. Conney, O-Methylation of tea polyphenols catalyzed by human placental cytosolic catechol-O-methyltransferase, Drug Metab. Dispos. 2000, 28, 1024 1030; H. Lu, X. Meng, C. S. Yang, Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by ()-epigallocatechin gallate, Drug Metab. Dispos. 2003, 31, 572 579. [22] D. Chen, C. Y. Wang, J. D. Lambert, N. Ai, W. J. Welsh, C. S. Yang, Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies, Biochem. Pharmacol. 2005, 69, 1523 1531; B. T. Zhu, E. L. Ezell, J. G. Liehr, Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids, J. Biol. Chem. 1994, 269, 292 299. [23] D. E. Stack, J. Byun, M. L. Gross, E. G. Rogan, E. L. Cavalieri, Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides, Chem. Res. Toxicol. 1996, 9, 851 859; J. L. Bolton, E. Pisha, F. Zhang, S. Qiu, Role of quinoids in estrogen carcinogenesis, Chem. Res. Toxicol. 1998, 11, 1113 1127; M. Zahid, E. Kohli, M. Saeed, E. Rogan, E. Cavalieri, The greater reactivity of estradiol-3,4-quinone vs. estradiol-2,3-quinone with DNA in the formation of depurinating adducts: implications for tumor-initiating activity, Chem. Res. Toxicol. 2006, 19, 164 172. , [24] L. C. Zacharia, C. A. Piche R. M. Fielding, K. M. Holland, S. D. Allison, R. K. Dubey, E. K. Jackson, 2-Hydroxyestradiol is a prodrug of 2-methoxyestradiol, J. Pharmacol. Exp. Ther. 2004, 309, 1093 1097. [25] D. M. Ziegler, S. S. Ansher, T. Nagata, F. F. Kadlubar, W. B. Jakoby, N-Methylation: potential mechanism for metabolic activation of carcinogenic primary arylamines, Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 2514 2517. [26] P. A. Crooks, C. S. Godin, L. A. Damani, S. S. Ansher, W. B. Jakoby, Formation of quaternary amines by N-methylation of azaheterocycles with homogenous amine N-methyltransferase. Biochem. Pharmacol. 1988, 37, 1673 1677. [27] G. Maret, B. Testa, P. Jenner, N. El Tayar, P. A. Carrupt, The MPTP story: MAO activates tetrahydropyridine derivatives to toxins causing parkinsonism, Drug Metab. Rev. 1990, 22, 291 332. [28] a) M. Naoi, S. Matsuura, T. Takahashi, T. Nagatsu, A N-methyltransferase in human brain catalyses N-methylation of 1,2,3,4-tetrahydroisoquinoline into N-methyl-1,2,3,4-tetrahydroisoquinoline, a precursor of a dopaminergic neurotoxin, N-methylisoquinolinium ion, Biochem. Biophys. Res. Commun. 1989, 161, 1213 1219; b) A. H. Bahnmaier, B. Woesle, H. Thomas, Stereospecific Nmethylation of the tetrahydroisoquinoline alkaloids isosalsoline and salsolidine by amine Nmethyltransferase A from bovine liver, Chirality 1999, 11, 160 165.
2309
[29] G. Ginsberg, D. Hattis, A. Russ, B. Sonawane, Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: implications for assessing childrens risks from environmental agents, J. Toxicol. Environ. Health, Part A 2004, 67, 297 329. [30] J. DSouza, J. Caldwell, R. L. Smith, Species differences in the N-methylation and quaternization of [14C]pyridine, Xenobiotica 1988, 10, 151 157. [31] K. C. Cundy, P. A. Brooks, C. S. Godin, Remarkable substrate-inhibitor properties of nicotine enantiomers towards a guinea pig lung aromatic azaheterocycle N-methyltransferase, Biochem. Biophys. Res. Commun. 1985, 128, 312 316. [32] J. Hukkanen, P. Jacob III, N. L. Benowitz, Metabolism and disposition of nicotine, Pharmacol. Rev. 2005, 57, 79 115; D. Yildiz, Nicotine, its metabolism and an overview of its biological effects, Toxicon 2004, 43, 619 632. [33] C. Szumlanski, D. Otterness, C. Her, D. Lee, B. Brandriff, D. Kelsell, N. Spurr, L. Lennard, E. Wieben, R. Weinshilboum, Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism, DNA Cell Biol. 1996, 15, 17 30; E. Y. Krynetski, W. E. Evans, Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm, Pharm. Res. 1999, 16, 342 349; R. Weinshilboum, Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase, Drug Metab. Dispos. 2001, 29, 601 605; H. Wei, S. Zhou, C. Li, J. Zhang, J. Wu, M. Huang, Phenotyping and genotyping studies of thiopurine S-methyltransferase in Kazaks, Pharm. Res. 2005, 22, 1762 1766. [34] M. A. Ferroni, P. C. Giulianotti, A. Pietrabissa, F. Mosca, R. Gomeni, G. M. Pacifici, Captopril methylation in human liver and kidney: interindividual variability, Xenobiotica 1996, 26, 877 882. [35] R. A. Iyer, J. Mitroka, B. Malhotra, S. Bonacorsi Jr., S. C. Waller, J. K. Rinehart, V. A. Roongta, K. Kripalani, Metabolism of [14C]omapatrilat, a sulfhydryl-containing vasopeptidase inhibitor in humans, Drug Metab. Dispos. 2001, 29, 60 69; R. A. Iyer, B. Malhotra, S. Khan, J. Mitroka, S. Bonacorsi Jr., S. C. Waller, J. K. Rinehart, K. Kripalani, Comparative biotransformation of radiolabeled [14C]omapatrilat and stable-labeled [13C2 ]omapatrilat after oral administration to rats, dogs, and humans, Drug Metab. Dispos. 2003, 31, 67 75. [36] J. C. M. Wait, N. Vaccharajani, B. Malhotra, M. Jemal, S. Khan, S. Bonacorsi Jr., J. K. Rinehart, R. A. Iyer, Metabolism of [14C]gemopatrilat after oral administration to rats, dogs, and humans, Drug Metab. Dispos. 2006, 34, 961 970. [37] H. Schupke, R. Hempel, G. Peter, R. Hermann, K. Wessel, J. Engel, T. Kronbach, New metabolic pathways of a-lipoic acid, Drug Metab. Dispos. 2001, 29, 855 862. [38] E. R. Wickremsinhe, Ye Tian, K. J. Ruterbories, E. M. Verburg, G. J. Weerakkody, A. Kurihara, N. A. Farid, Stereoselective metabolism of prasugrel in humans using a novel chiral liquid chromatography-tandem mass spectrometry method, Drug Metab. Dispos. 2007, 35, 917 921; N. A. Farid, R. L. Smith, T. A. Gillespie, T. J. Rash, R. E. Blair, A. Kurihara, M. J. Goldberg, The disposition of prasugrel, a novel thienopyridine, in humans, Drug Metab. Dispos. 2007, 35, 1096 1104; J. L. F. Rehmel, J. A. Eckstein, N. A. Farid, J. B. Heim, S. C. Kasper, A. Kurihara, S. A. Wrighton, B. J. Ring, Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450, Drug Metab. Dispos. 2006, 34, 600 607. [39] R. E. Staub, S. E. Sparks, G. B. Quistad, J. E. Cassida, S-Methylation as a bioactivation mechanism for mono- and dithiocarbamate pesticides as aldehyde dehydrogenase inhibitors, Chem. Res. Toxicol. 1995, 8, 1063 1069. [40] H. V. Aposhian, Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity, Annu. Rev. Pharmacol. Toxicol. 1997, 37, 397 419; H. V. Aposhian, M. M. Aposhian, Arsenic toxicology: five questions, Chem. Res. Toxicol. 2006, 19, 1 15. [41] M. J. Mass, A. Tennant, B. C. Roop, W. R. Cullen, M. Styblo, D. J. Thomas, A. D. Kligerman, Methylated trivalent arsenic species are genotoxic, Chem. Res. Toxicol. 2001, 14, 355 361; T. Sakurai, W. Qu, M. H. Sakurai, M. P. Waalkes, A major human arsenic metabolite, dimethylarsinic acid, requires reduced glutathione to induce apoptosis, Chem. Res. Toxicol. 2002, 15, 629 637; P. Andrewes, K. T. Kitchin, K. Wallace, Dimethylarsine and trimethylarsine are potent genotoxins in vitro, Chem. Res. Toxicol. 2003, 16, 994 1003; T. J. Patterson, M. Ngo, P. A. Aronov, T. V.
2310
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49] [50]
[51] [52]
Reznikova, P. G. Green, R. H. Rice, Biological activity of inorganic arsenic and antimony reflects oxidation state in cultured human keratinocytes, Chem. Res. Toxicol. 2003, 16, 1624 1631. S. Nesnow, B. C. Roop, G. Lambert, M. Kadiiska, R. P. Mason, W. R. Cullen, M. J. Mass, DNA damage induced by methylated trivalent arsenicals is mediated by reactive oxygen species, Chem. Res. Toxicol. 2002, 15, 1627 1634. S. V. Kala, G. Kala, C. I. Prater, A. C. Sartorelli, M. W. Lieberman, Formation and urinary excretion of arsenic triglutathione and methylarsenic diglutathione, Chem. Res. Toxicol. 2004, 17, 243 249; H. R. Hansen, A. Raah, M. Jaspars, B. F. Milne, J. Feldmann, Sulfur-containing arsenical mistaken for dimethylarsinous acid [DMA(III)] and identified as a natural metabolite in urine: major implications for studies on arsenic metabolism and toxicity, Chem. Res. Toxicol. 2004, 17, 1086 1091; H. Naranmandura, N. Suzuki, K. Iwata, S. Hirano, K. T. Suzuki, Arsenic metabolism and thioarsenicals in hamsters and rats, Chem. Res. Toxicol. 2007, 20, 616 624. H. V. Aposhian, E. S. Gurzau, X. C. Lee, A. Gurzau, S. M. Healy, X. Lu, M. Ma, L. Yip, R. A. Zakharyan, R. M. Maiorino, R. C. Dart, M. G. Tircus, D. Gonzalez-Ramirez, D. L. Morgan, D. Avram, M. M. Aposhian, Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic, Chem. Res. Toxicol. 2000, 13, 693 697; B. K. Mandal, Y. Ogra, K. T. Suzuki, Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenicaffected areas in West Bengal, India, Chem. Res. Toxicol. 2001, 14, 371 378. M. Styblo, L. M. Del Razo, E. L. LeCluyse, G. A. Hamilton, C. Wang, W. R. Cullen, D. J. Thomas, Metabolism of arsenic in primary cultures of human and rat hepatocytes, Chem. Res. Toxicol. 1999, 12, 560 565. M. Styblo, H. Yamauchi, D. J. Thomas, Comparative in vitro methylation of trivalent and pentavalent arsenicals, Toxicol. Appl. Pharmacol. 1995, 135, 172 178; R. A. Zakharyan, Y. Wu, G. M. Bogdan, H. V. Aposhian, Enzymatic methylation of arsenic compounds: assay, partial purification, and properties of arsenite methyltransferase and monomethylarsonic acid methyltransferase of rabbit liver, Chem. Res. Toxicol. 1995, 8, 1029 1038; T. C. Wood, O. E. Salavagionne, B. Mukherjee, L. Wang, A. F. Klumpp, B. A. Thomae, B. W. Eckloff, D. J. Schaid, E. D. Wieben, R. M. Weinshilboum, Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies, J. Biol. Chem. 2006, 281, 7364 7373. D. J. Thompson, A chemical hypothesis for arsenic methylation in mammals, Chem.-Biol. Interact. 1993, 88, 89 114; R. A. Zakharyan, G. Tsaprailis, U. K. Chowdhury, A. Hernandez, H. V. Aposhian, Interactions of sodium selenite, glutathione, arsenic species, and omega human glutathione transferase, Chem. Res. Toxicol. 2005, 18, 1287 1295. R. A. Zakharyan, A. Sampayao-Reyes, S. M. Healy, G. Tsaprailis, P. G. Board, D. C. Liebler, H. V. Aposhian, Human monomethylarsonic acid (MMAV ) reductase is a member of the glutathione-Stransferase superfamily, Chem. Res. Toxicol. 2001, 14, 1051 1057; T. R. Radabaugh, A. SampayoReyes, R. A. Zakharyan, H. V. Aposhian, Arsenate reductase II. Purine nucleoside phosphorylase in the presence of dihydrolipoic acid is a route for reduction of arsenate to arsenite in mammalian systems, Chem. Res. Toxicol. 2002, 15, 692 698; L. L. Marnell, G. G. Garcia-Vargas, U. K. Chowdhury, R. A. Zakharyan, B. Walsh, M. D. Avram, M. J. Kopplin, M. E. Cebrian, E. K. Silbergeld, H. V. Aposhian, Polymorphism in the human monomethylarsonic acid (MMAV ) reductase/hGST01 gene and changes in urinary arsenic profiles, Chem. Res. Toxicol. 2003, 16, 1507 1513. H. Naranmandura, N. Suzuki, K. T. Suzuki, Trivalent arsenicals are bound to proteins during reductive methylation, Chem. Res. Toxicol. 2006, 19, 1010 1018. M. W. H. Coughtrie, M. B. Fisher, The role of sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs) in human drug clearance and bioactivation, in Drug Metabolizing Enzymes: Cytochrome P450 and Other Enzymes in Drug Discovery and Development, Eds. J. Lee, R. S. Obach, M. B. Fisher, Dekker, New York, 2003, p. 541 575. F. C. Kauffman, Sulfonation in Pharmacology and Toxicology, Drug Metab. Rev. 2004, 36, 823 843. R. B. Raftogianis, T. C. Wood, R. M. Weinshilboum, Human phenol sulfotransferases SULT1A2 and SULT1A1, Biochem. Pharmacol. 1999, 58, 605 616; K. Nagata, Y. Yamazoe, Pharmacogenetics of sulfotransferases, Annu. Rev. Pharmacol. Toxicol. 2000, 40, 159 176; R. L. Blanchard,
2311
[53]
[54]
[55]
[56] [57] [58]
[59]
[60]
[61]
[62]
[63]
[64] [65]
R. R. Freimuth, J. Buck, R. M. Weinshilboum, M. W. Coughtrie, A proposed nomenclature system for the cytosolic sulfotransferase (SULT) superfamily, Pharmacogenetics 2004, 14, 199 211; J. G. Slatter, I. E. Templeton, J. C. Castle, A. Kulkarni, T. H. Rushmore, K. Richards, Y. He, X. Dai, O. J. Cheng, M. Caguyong, R. G. Ulrich, Compendium of gene expression profiles comprizing a baseline model of the human liver drug metabolism transcriptome, Xenobiotica 2006, 36, 938 962. H. Glatt, H. Boeing, C. E. Engelke, L. Ma, A. Kuhlow, U. Pabel, D. Pomplun, W. Teubner, W. Meinl, Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects, Mutat. Res. 2001, 482, 27 40; M. W. H. Coughtrie, L. E. Johnston, Interactions between dietary chemicals and human sulfotransferases Molecular mechanisms and clinical significance, Drug Metab. Dispos. 2001, 29, 522 528; C. Tsoi, S. Swedmark, Sulfation in dogs, Curr. Drug Metab. 2005, 6, 275 285. M. Runge-Morris, T. A. Kocarek, Regulation of sulfotransferases by xenobiotic receptors, Curr. Drug Metab. 2005, 6, 299 307; S. Maiti, J. Zhang, G. Chen, Redox regulation of human estrogen sulfotransferase (hSULT1E1), Biochem. Pharmacol. 2007, 73, 1474 1481. J. I. Armstrong, C. R. Bertozzi, Sulfotransferases as targets for therapeutic intervention, Curr. Opin. Drug Discovery Dev. 2000, 3, 502 515; Y. Kakuta, E. V. Petrotchenko, L. C. Pedersen, M. Negishi, The sulfuryl transfer mechanism, J. Biol. Chem. 1998, 273, 27325 27330. N. U. Gamage, S. Tsvetanov, R. G. Duggleby, M. E. McManus, J. L. Martin, The structure of human SULT1A1 crystallized with estradiol, J. Biol. Chem. 2005, 280, 41482 41486. G. Chen, Histidine residues in human phenol sulfotransferases, Biochem. Pharmacol. 2004, 67, 1355 1361. K. P. Wong, B. Y. Khoo, K. H. Sit, Biosynthesis of PAPS in vitro by human liver, Biochem. Pharmacol. 1991, 41, 63 69; T. S. Leyh, The physical biochemistry and molecular genetics of sulfate activation, Crit. Rev. Biochem. Mol. Biol. 1993, 28, 515 542; H. J. Kim, J. H. Cho, C. D. Klaasen, Depletion of hepatic 3-phosphoadenosine 5-phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated, J. Pharmacol. Exp. Ther. 1995, 275, 654 658. A. Pedretti, L. Villa, G. Vistoli, VEGA: a versatile program to convert, handle and visualize molecular structure on windows-based PCs, J. Mol. Graphics 2002, 21, 47 49 (www.ddl.unimi.it); VMD, www.ks.uiuc.edu/Research/vmd; POVRay, www.povray.org. C. A. Tabrett, M. W. H. Coughtrie, Phenol sulfotransferase 1A1 activity in human liver: kinetic properties, interindividual variation and re-evaluation of the suitability of 4-nitrophenol as a substrate probe, Biochem. Pharmacol. 2003, 66, 2089 2097; Z. Riches, J. C. Bloomer, M. W. H. Coughtrie, Comparison of 2-aminophenol and 4-nitrophenol as in vivo probe substrates for the major human hepatic sulfotransferase, SULT1A1, demonstrates improved selectivity with 2aminophenol, Biochem. Pharmacol. 2007, 74, 352 358. N. R. C. Campbell, J. A. Van Loon, R. S. Sundaram, M. M. Ames, C. Hansch, R. Weinshilboum, Human and rat liver phenol sulfotransferase: structure-activity relationships for phenolic substrates, Mol. Pharmacol. 1987, 32, 813 819; M. H. Parker, D. J. McCann, J. B. Mangold, Sulfation of di- and tricyclic phenols by rat liver aryl sulfotransferase isozymes, Arch. Biochem. Biophys. 1994, 310, 325 331. Y. Liu, T. I. Apak, H.-J. Lehmler, L. W. Robertson, M. W. Duffel, Hydroxylated polychlorinated biphenyls are substrates and inhibitors of human hydroxysteroid sulfotransferase SULT2A1, Chem. Res. Toxicol. 2006, 19, 1420 1425; Y. Nakagawa, T. Suzuki, H. Ishii, A. Ogata, Biotransformation and cytotoxicity of a brominated flame retardant, tetrabromobisphenol A, and its analogues in rat hepatocytes, Xenobiotica 2007, 37, 693 708; L. N. Vandenberg, R. Hauser, M. Marcus, N. Olea, W. V. Welshons, Human exposure to bisphenol A (BPA), Reprod. Toxicol. 2007, 24, 139 177. K. Itaho, S. Alakurtti, J. Yli-Kauhaluoma, J. Taskinen, M. W. H. Coughtrie, R. Kosiainen, Regioselective sulfonation of dopamine by SULT1A3 in vitro provides a molecular explanation for the preponderance of dopamine-3-O-sulfate in human blood circulation, Biochem. Pharmacol. 2007, 74, 504 510. D. Ung, S. Nagar, Variable sulfation of dietary polyphenols by recombinant human sulfotransferase (SULT) 1A1 genetic variants and SULT1E1, Drug Metab. Dispos. 2007, 35, 740 746. M. Miksits, A. Maier-Salamon, S. Aust, T. Thalhammer, G. Reznick, O. Kunert, E. Haslinger, T. Szekeres, W. Jaeger, Sulfation of resveratrol in human liver: evidence of a major role for the
2312
[66]
[67]
[68]
[69]
[70]
[71]
[72] [73]
[74] [75]
[76]
[77]
[78]
sulfotransferases SULT1A1 and SULT1E1, Xenobiotica 2005, 35, 1101 1119; C. Yu, Y. G. Shin, A. Chow, Y. Li, J. W. Kosmeder, Y. S. Lee, W. H. Hirschelman, J. M. Pezzuto, R. G. Mehta, R. B. van Breemen, Human, rat, and mouse metabolism of resveratrol, Pharm. Res. 2002, 19, 1907 1914. G. R. Pesola, T. Walle, Stereoselective sulfate conjugation of isoproterenol in humans: comparison of hepatic, intestinal, and platelet activity, Chirality 1993, 5, 602 609; A. P. Hartman, A. A. Wilson, H. M. Wilson, G. Aberg, C. N. Falany, T. Walle, Enantioselective sulfation of b2-receptor agonists by the human intestine and the recombinant M-form phenolsulfotransferase, Chirality 1998, 10, 800 803. G. Chen, E. Banoglu, M. W. Duffel, Influence of substrate structure on the catalytic efficiency of hydroxysteroid sulfotransferase STa in the sulfation of alcohols, Chem. Res. Toxicol. 1996, 9, 67 74; E. Banoglu, M. W. Duffel, Studies on the interactions of chiral secondary alcohols with rat hydroxysteroid sulfotransferase STa, Drug Metab. Dispos. 1997, 25, 1304 1310; E. Banoglu, M. W. Duffel, Importance of peri-interactions on the stereospecificity of rat hydroxysteroid sulfotransferase STa with 1-arylethanols, Chem. Res. Toxicol. 1999, 12, 278 285. D. Cui, G. O. Rankin, P. J. Harvison, Metabolism of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide in rats: evidence for bioactivation through alcohol-O-glucuronidation and O-sulfation, Chem. Res. Toxicol. 2005, 18, 991 1003. R. S. Tsai, P. A. Carrupt, B. Testa, J. Caldwell, Structure-genotoxicity relationships of allylbenzenes and propenylbenzenes: A quantum-chemical study, Chem. Res. Toxicol. 1994, 7, 73 76 (correction 1995, 8, 164). J. A. Miller, Sulfonation in chemical carcinogenesis history and present status, Chem.-Biol. Interact. 1994, 92, 329 341; Y.-J. Surh, J. A. Miller, Roles of electrophilic sulfuric ester metabolites in mutagenesis and carcinogenesis by some polynuclear aromatic hydrocarbons, Chem.-Biol. Interact. 1994, 92, 351 362. T. Watabe, K. Ogura, M. Satsukawa, H. Okuda, A. Hiratsuka, Molecular cloning and functions of rat liver hydroxysteroid sulfostranferases catalysing covalent binding of carcinogenic arylmethanols to DNA, Chem.-Biol. Interact. 1994, 92, 87 105. E. Banoglu, Current status of the cytosolic sulfotransferases in the metabolic activation of promutagens and procarcinogens, Curr. Drug Metab. 2000, 1, 1 30. R. S. King, V. Sharma, L. C. Pedersen, Y. Kakuta, M. Negishi, M. W. Duffel, Structure-function modeling of the interactions of N-alkyl-N-hydroxyanilines with rat hepatic aryl sulfotransferase IV, Chem. Res. Toxicol. 2000, 13, 1251 1258. J. P. Chism, D. E. Rickert, Isomer- and sex-specific bioactivation of mononitrotoluenes. Role of enterohepatic circulation, Drug Metab. Dispos. 1985, 13, 651 657. a) J. H. N. Meerman, D. P. Ringer, M. W. H. Coughtrie, K. J. Bamforth, R. A. H. J. Gilissen, Sulfation of carcinogenic aromatic hydroxylamines and hydroxamic acids by rat and human sulfotransferases: substrate specificity, developmental aspects and sex differences, Chem.-Biol. Interact. 1994, 92, 321 328; b) A. J. Lewis, Y. Otake, U. K. Walle, T. Walle, Sulphonation of Nhydroxy-2-acetylaminofluorene by human dehydroepiandrosterone sulphotransferase, Xenobiotica 2000, 30, 253 261. B. Clement, K. Christiansen, U. Girreser, Phase 2 metabolites of N-hydroxylated amidines (amidoximes): synthesis, in vitro formation by pig hepatocytes, and mutagenicity testing, Chem. Res. Toxicol. 2001, 14, 319 326. K. D. Meisheri, G. A. Johnson, L. Puddington, Enzymatic and nonenzymatic sulfation mechanisms in the biological actions of minoxidil, Biochem. Pharmacol. 1993, 45, 271 279; S. S. Singer, The same enzymes catalyze sulfation of minoxidil, minoxidil analogs and catecholamines, Chem.-Biol. Interact. 1994, 92, 33 45. D. K. Dalvie, N. Khosla, J. Vincent, Excretion and metabolism of trovafloxacin in humans, Drug Metab. Dispos. 1997, 25, 423 427; D. K. Dalvie, N. Khosla, K. A. Navetta, K. E. Brighty, Metabolism and excretion of trovafloxacin, a new quinolone antibiotic, in rats and dogs, Drug Metab. Dispos. 1996, 24, 1231 1240.
2313
[79] T. Shiraga, T. Hata, Y. Yamazoe, Y. Ohno, K. Iwasaki, N-Sulphoconjugation of amines by human cytosolic hydroxysteroid sulphotransferase, Xenobiotica 1999, 29, 341 347; S. G. Ramaswamy, W. B. Jakoby, Amine N-sulfotransferase, J. Biol. Chem. 1987, 262, 10039 10043. [80] K. O. Wong, K. P. Wong, N-Sulphation of desipramine in the rat brain, Xenobiotica 1996, 26, 17 26; K. Iwasaki, T. Shiraga, K. Noda, K. Tada, H. Noguchi, S-Sulphoconjugation of alicyclic, alkyland aryl-amines in vivo and in vitro, Xenobiotica 1986, 16, 651 659. [81] J. M. Sanders, L.-J. Chen, L. T. Burka, H. B. Matthews, Metabolism and disposition of luminol in the rat, Xenobiotica 2000, 30, 263 272. [82] C. Zhu, M. Johansson, J. Permert, A. Karlsson, Phosphorylation of anticancer nucleotide analogs by human mitochondrial deoxyguanosine kinase, Biochem. Pharmacol. 1998, 56, 1035 1040; J. Y. Feng, W. B. Parker, M. L. Krajewski, D. Deville-Bonne, M. Veron, P. Krishnan, Y.-C. Cheng, K. Borroto-Esoda, Anabolism of amdoxovir: phosphorylation of dioxolane guanosine and its 5phosphates by mammalian phosphotransferases, Biochem. Pharmacol. 2004, 68, 1879 1888; T. Ben-Kasus, Z. Ben-Zvi, V. E. Marquez, J. A. Kelley, R. Agbaria, Metabolic activation of zebularine, a novel DNA methylation inhibitor, in human bladder carcinoma cells, Biochem. Pharmacol. 2005, 70, 121 133. [83] K. Peters, J. G. Gambertoglio, Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus, Clin. Pharmacol. Ther. 1996, 60, 168 176; M. D. Lynx, E. E. McKee, 3-Azido-3-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria, Biochem. Pharmacol. 2006, 72, 239 243. [84] R. Albert, K. Hinterding, V. Brinkmann, D. Guerini, C. Mller-Hartwieg, H. Knecht, C. Simeon, M. Streiff, T. Wagner, K. Welzenbach, F. Zecri, M. Zollinger, N. Cooke, E. Francotte, Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomers, J. Med. Chem. 2005, 48, 5373 5377. [85] H. K. Kroemer, U. Klotz, Glucuronidation of drugs A re-evaluation of the pharmacological significance of the conjugates and modulating factors, Clin. Pharmacokinet. 1992, 23, 292 310; G. J. Mulder, Glucuronidation and its role in regulation of biological activity of drugs, Annu. Rev. Pharmacol. Toxicol. 1992, 32, 25 49; J. O. Miners, P. J. McKenzie, Drug glucuronidation in humans, Pharmacol. Ther. 1991, 51, 347 369. [86] Y. Giroud, P. A. Carrupt, A. Pagliara, B. Testa, R. G. Dickinson, Intrinsic and intramolecular lipophilicity effects in O-glucuronides, Helv. Chim. Acta 1998, 81, 330 341. [87] A. Pagliara, P. A. Carrupt, G. Caron, P. Gaillard, B. Testa, Lipophilicity profiles of ampholytes, Chem. Rev. 1997, 97, 3385 3400. [88] B. Burchell, M. W. H. Coughtrie, UDP-Glucuronosyltransferases, Pharmacol. Ther. 1989, 43, 261 289; R. H. Tuckey, C. P. Strassburg, Human UDP-glucuronosyltransferases: metabolism, expression, and disease, Annu. Rev. Pharmacol. Toxicol. 2000, 40, 581 616; C. Guillemette, Pharmacogenomics of human UDP-glucuronosyltransferase enzymes, Pharmacogenomics J. 2003, 3, 136 158; K. W. Bock, Vertebrate UDP-glucuronosyltransferases: functional and evolutionary aspects, Biochem. Pharmacol. 2003, 66, 691 696. [89] http://som.flinders.edu.au/FUSA/ClinPharm/UGT/; P. I. Mackenzie, K. W. Bock, B. Burchell, C. Guillemette, S.-I. Ikushiro, T. Iyanagi, J. O. Miners, I. S. Owens, D. W. Nebert, Nomenclature update for the mammalian UDP-glycosyltransferase (UGT) gene superfamily, Pharmacogenet. Genomics 2005, 15, 677 685; P. I. Mackenzie, I. S. Owens, B. Burchell, K. W. Bock, A. Bairoch, A. Belanger, S. Fournel-Gigleux, M. Green, D. W. Hum, T. Iyanagi, D. Lancet, P. Louisot, J. Magdalou, J. R. Chowdhury, J. K. Ritter, H. Schachter, T. R. Tephly, K. F. Tipton, D. W. Nebert, The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence, Pharmacogenetics 1997, 7, 255 269. [90] P. Wells, P. I. Mackenzie, J. R. Chowdhury, C. Guillemette, P. A. Gregory, Y. Ishii, A. J. Hansen, F. K. Kessler, P. M. Kim, N. R. Chowdhury, J. K. Ritter, Glucuronidation and the UDP-glucuronosyltransferases in health and disease, Drug Metab. Dispos. 2004, 32, 281 290; A. Radominska-Pandya, S. Bratton, J. M. Little, A historical overview of the heterologous expression of mammalian UDP-
2314
[91]
[92] [93]
[94]
[95] [96]
[97]
[98]
[99]
[100]
[101]
glucuronosyltransferase isoforms over the last twenty years, Curr. Drug Metab. 2005, 6, 141 160. M. B. Fisher, M. F. Paine, T. J. Strelevitz, S. A. Wrighton, The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism, Drug Metab. Rev. 2001, 33, 273 297; R. H. Tuckey, C. P. Strassburg, Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract, Mol. Pharmacol. 2001, 59, 405 414; K. A. McGurk, C. H. Brierley, B. Burchell, Drug glucuronidation by human renal UDP-glucuronosyltransferases, Biochem. Pharmacol. 1998, 55, 1005 1012. T. Tephly, M. Green, J. Puig, Y. Irshaid, Endogenous substrates for UDP-glucuronosyltransferases, Xenobiotica 1988, 18, 1201 1210. Y. Maruo, M. Iwai, A. Mori, H. Sato, Y. Takeuchi, Polymorphism of UDP-glucuronosyltransferases and drug disposition, Curr. Drug Metab. 2005, 6, 91 99; Y. Chen, S. Chen, X. Li, X. Wang, S. Zeng, Genetic variants of human UGT1A3: functional characterization and frequency distribution in a Chinese Han population, Drug Metab. Dispos. 2006, 34, 1462 1467. H. Tian, J. Ou, S. C. Strom, R. Venkataramanan, Activity and expression of various isoforms of UDP-glucuronosyltransferases are differently regulated during hepatic regeneration in rats, Pharm. Res. 2005, 22, 2007 2015; J. Zhou, J. Zhang, W. Xie, Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosyltransferases, Curr. Drug Metab. 2005, 6, 289 298. B.-K. Tang, Drug glucosidation, Pharmacol. Ther. 1990, 46, 53 56. A. Radominska-Pandya, P. J. Czernik, J. M. Little, E. Battaglia, P. I. Mackenzie, Structural and functional studies of UDP-glucuronosyltransferases, Drug Metab. Rev. 1999, 31, 817 899; J. O. Miners, K. M. Knights, J. B. Houston, P. I. Mackenzie, In vitro-in vivo correlation for drug and other compounds eliminated by glucuronidation in humans: pitfalls and promises, Biochem. Pharmacol. 2006, 71, 1531 1539; B. C. Lewis, P. I. Mackenzie, D. J. Elliot, B. Burchell, C. R. Bhasker, J. O. Miners, Amino terminal domains of human UDP-glucuronosyltransferases (UGT) 2B7 and 2B15 associated with substrate selectivity and autoactivation, Biochem. Pharmacol. 2007, 73, 1463 1473; C. W. Locuson, T. S. Tracy, Comparative modelling of the human UDP-glucuronosyltransferases: insights into structure and mechanism, Xenobiotica 2007, 37, 155 168. P. A. Smith, M. J. Sorich, R. A. McKinnon, J. O. Miners, Pharmacophore and QSAR modeling: complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity, J. Med. Chem. 2003, 46, 1617 1626; M. J. Sorich, R. A. McKinnon, J. O. Miners, D. A. Winkler, P. A. Smith, Rapid prediction of chemical metabolism by human UDPglucuronosyltransferase isoforms using quantum-chemical descriptors derived with the electronegativity equalization method, J. Med. Chem. 2004, 47, 5311 5317; J. O. Miners, P. A. Smith, M. J. Sorich, R. A. McKinnon, P. I. Mackenzie, Predicting human drug glucuronidation parameters: application of in vitro and in silico modeling approaches, Annu. Rev. Pharmacol. Toxicol. 2004, 44, 1 25; M. J. Sorich, J. O. Miners, R. A. McKinnon, P. A. Smith, Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substrate selectivity, Mol. Pharmacol. 2004, 65, 301 308. M. J. Miley, A. K. Zielinska, J. E. Keenan, S. M. Bratton, A. Radominska-Pandya, M. R. Redinbo, Crystal structure of the cofactor-binding domain of the human phase II drug-metabolism enzyme UDP-glucuronosyltransferase 2B7, J. Mol. Biol. 2007, 369, 498 511. R. H. Lewinsky, P. A. Smith, P. I. Mackenzie, Glucuronidation of bioflavonoids by human UGT1A10: structure-function relationships, Xenobiotica 2005, 35, 117 129; J. Taskinen, B. T. Ethell, P. Puhlavisto, A. M. Hood, B. Burchell, M. W. H. Coughtrie, Conjugation of catechols by recombinant human sulfotransferases, UDP-glucuronosyltransferases, and soluble catechol Omethyltransferase: structure-conjugation relationships and predictive models, Drug Metab. Dispos. 2003, 31, 1187 1197. S. S. Brill, A. M. Furimsky, M. N. Ho, M. J. Furniss, Y. Lim A. G. Green, W. W. Bradford, C. E. Green, I. M. Kapetanovic, L. V. Iyer, Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms, J. Pharm. Pharmacol. 2006, 58, 469 479. L. Zhang, G. Lin, Z. Zuo, Involvement of UGT-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoids, Pharm. Res. 2006, 24, 81 89; L. Zhang, Z. Zuo, G.
2315
[102]
[103]
[104]
[105]
[106] [107] [108]
[109]
[110]
Lin, Intestinal and hepatic glucuronidation of flavonoids, Mol. Pharmaceutics 2007, 4, 833 845; S. W. J. Wang, J. Chen, X. Jia, V. H. Tam, M. Hu, Disposition of flavonoids via enteric recycling: structural effects and lack of correlations between in vitro and in situ metabolic properties, Drug Metab. Dispos. 2006, 34, 1837 1848; X. Liu, V. H. Tam, M. Hu, Disposition of flavonoids via enteric recycling: determination of the UGT-glucuronosyltransferase isoforms responsible for the metabolism of flavonoids in intact Caco-2 TC7 cells using siRNA, Mol. Pharmaceutics 2007, 4, 873 882. M. G. Boersma, H. van der Woude, J. Bogaars, S. Boeren, J. Vervoort, N. H. P. Cnubben, M. L. P. S. van Iersel, P. J. van Bladeren, I. M. C. M. Rietjens, Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyltransferases, Chem. Res. Toxicol. 2002, 15, 662 670; H. van der Woude, M. G. Boersma, J. Vervoort, I. M. C. M. Rietjens, Identification of 14 quercetin phase II mono- and mixed conjugates and their formation by rat and human phase II in vitro model systems, Chem. Res. Toxicol. 2004, 17, 1520 1530; Y. K. Chen, S. Q. Chen, X. li, S. Zheng, Quantitative regioselectivity of glucuronidation of quercetin by recombinant UDP-glucuronosyltransferases 1A9 and 1A3 using enzymatic kinetic parameters, Xenobiotica 2005, 35, 943 954. R. W. Milne, R. L. Nation, A. A. Somogyi, The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine, Drug Metab. Rev. 1996, 28, 345 472; B. L. Coffman, M. R. Kearney, S. Goldsmith, B. M. Knosp, T. R. Tephly, Opioids bind to the amino acids 84 to 118 of UDPglucuronosyltransferase UGT2B7, Mol. Pharmacol. 2003, 63, 283 288. M. H. Court, S. X. Duan, L. L. von Moltke, D. J. Greenblatt, C. J. Patten, J. O. Miners, P. I. Mackenzie, Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms, J. Pharmacol. Exp. Ther. 2001, 299, 998 1006; A. E. Mutlib, T. C. Goosen, J. N. Bauman, J. A. Williams, S. Kulkarni, S. Kostrubsky, Kinetics of acetaminophen glucuronidation by UDPglucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminopheninduced hepatotoxicity, Chem. Res. Toxicol. 2006, 19, 701 709; F. K. Kessler, M. R. Kessler, D. J. Auyeung, J. K. Ritter, Glucuronidation of acetaminophen catalyzed by multiple rat phenol UDPglucuronosyltransferases, Drug Metab. Dispos. 2002, 30, 324 330; H. Wong, J. E. Grace Jr., M. R. Wright, M. R. Browning, S. J. Grassman, S. A. Bai, D. D. Christ, Glucuronidation in the chimpazee (Pan troglodytes): studies with acetaminophen, oestradiol and morphine, Xenobiotica 2006, 36, 1178 1190. A. Ghosal, N. Hapangama, Y. Yuan, J. Achanfuo-Yeboah, R. Iannucci, S. Chowdhury, K. Alton, J. E. Patrick, S. Zbaida, Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia), Drug Metab. Dispos. 2004, 32, 314 320. T. B. Vree, C. J. Timmer, Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women, J. Pharm. Pharmacol. 1998, 50, 857 864. B. Testa, J. M. Mayer. Hydrolysis in Drug and Prodrug Metabolism Chemistry, Biochemistry, and Enzymology, Verlag Helvetica Chimica Acta, Zurich, and Wiley-VCH, Weinheim, 2003. R. T. Swank, E. K. Novak, L. Zhen, Genetic regulation of the subcellular localization and expression of glucuronidase, in Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, Ed. F. C. Kauffman, Springer, Berlin, 1994, p. 131 160. T. Kuuranne, M. Kurkela, M. Thevis, W. Schnzer, M. Finel, R. Kostiainen, Glucuronidation of anabolic androgenic steroids by recombinant human UDP-glucuronosyltransferases, Drug Metab. Dispos. 2003, 31, 1117 1124; T. Murai, N. Samata, H. Iwabuchi, T. Ikeda, Human UDPglucuronosyltransferase, UGT1A8, glucuronidates dihydrotestosterone to a monoglucuronide and further to a structurally novel diglucuronide, Drug Metab. Dispos. 2006, 34, 1102 1108; T. Murai, H. Iwabuchi, T. Ikeda, Repeated glucuronidation at one hydroxyl group leads to structurally novel diglucuronides of steroid sex hormones, Drug Metab. Pharmacokinet. 2005, 20, 282 293. M. D. Green, D. J. Clarke, E. M. Oturu, P. B. Styczynski, M. R. Jackson, B. Burchell, T. R. Tephly, Cloning and expression of rat liver phenobarbital-inducible UDP-glucuronosyltransferase (2B12) with specificity for monoterpinoids alcohols, Arch. Biochem. Biophys. 1995, 322, 460 468; M. D.
2316
[111]
[112]
[113] [114]
[115]
[116]
[117] [118]
[119]
[120]
[121]
Green, T. R. Tephly, Glucuronidation of amines and hydroxylated xenobiotics and endobiotics catalyzed by expressed human UGT1.4 protein, Drug Metab. Dispos. 1996, 24, 356 363. M. Chen, D. Howe, B. Leduc, S. Kerr, D. A. Williams, Identification and characterization of two chloramphenicol glucuronides from the in vitro glucuronidation of chloramphenicol in human liver microsomes, Xenobiotica 2007, 37, 954 971. a) I. J. Martin, R. J. Lewis, M. A. Bernstein, I. G. Beattie, C. A. Martin, R. J. Riley, B. Springthorpe, Which hydroxy? Evidence for species differences in the regioselectivity of glucuronidation in rat, dog, and human in vitro systems and dog in vivo, Drug Metab. Dispos. 2006, 34, 1502 1507; b) O. Barbier, D. Turgeon, C. Girard, M. D. Green, T. R. Tephly, D. W. Hum, A. Belanger, 3-Azido-3deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7), Drug Metab. Dispos. 2000, 28, 497 502. A. Amberg, U. Bernauer, D. Scheutzow, W. Dekant, Biotransformation of [12C]- and [13C]-tert-amyl methyl ether and tert-amyl alcohol, Chem. Res. Toxicol. 1999, 12, 958 964. T. Sten, S. Qvisen, P. Uutela, L. Luukkanen, R. Kostiainen, M. Finel, Prominent but reverse stereoselectivity in propranolol glucuronidation by human UDP-glucuronosyltransferases 1A9 and 1A10, Drug Metab. Dispos. 2006, 34, 1488 1494. B. Testa, P. A. Carrupt, J. Gal, The so-called interconversion of stereoisomeric drugs: an attempt at clarification, Chirality 1993, 5, 105 111; M. Reist, B. Testa, P. A. Carrupt, Drug racemization and its significance in pharmaceutical research, in Stereochemical Aspects of Drug Action and Disposition, Eds. M. Eichelbaum, B. Testa, A. Somogyi, Springer Verlag, Berlin, 2003, p. 91 112. M. H. Court, S. X. Duan, C. Guillemette, K. Journault, S. Krishnaswamy, L. L. von Moltke, D. J. Greenblatt, Stereoselective conjugation of oxazepam by human UDP-glucuronosyltransferases (UGTs): S-oxazepam is glucuronidated by UGT2B15, while R-oxazepam is glucuronidated by UGT2B7 and UGT1A9, Drug Metab. Dispos. 2002, 30, 1257 1265; M. H. Court, Q. Hao, S. Krishnaswamy, T. Bekaii-Saab, A. Al-Rohaimi, L. L. von Moltke, D. J. Greenblatt, UDPGlucuronosyltransferase (UGT) 2B15 pharmacogenetics: UGT2B15 D85Y genotype and gender are major determinants of oxazepam glucuronidation by human liver, J. Pharmacol. Exp. Ther. 2004, 310, 656 665. R. R. Miller, G. A. Doss, R. A. Stearns, Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent, Drug Metab. Dispos. 2004, 32, 178 185. D. J. Sweeny, J. Bouska, J. Machinist, R. Bell, G. Carter, S. Cepa, H. N. Nellans, Glucuronidation of zileuton (A-64077) by human hepatic microsomes, Drug Metab. Dispos. 1992, 20, 328 329; D. J. Sweeny, H. N. Nellans, Stereoselective glucuronidation of zileuton isomers by human hepatic microsomes, Drug Metab. Dispos. 1995, 23, 149 153; S. L. Wong, W. M. Awni, J. H. Cavanaugh, T. , el-Shourbagy, C. S. Locke, L. M. Dube The pharmacokinetics of single oral doses of zileuton 200 to 800 mg, its enantiomers, and its metabolites, in normal healthy volunteers, Clin. Pharmacokinet. 1995, 29 (Suppl. 2), 9 21. E. M. Faed, Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drugs, Drug Metab. Rev. 1984, 15, 1213 1249; M. Spahn-Langguth, L. Z. Benet, Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism?, Drug Metab. Rev. 1992, 24, 5 48; A. V. Stachulski, J. R. Harding, J. C. Lindon, J. L. Maggs, B. K. Park, I. D. Wilson, Acyl glucuronides: biological activity, chemical reactivity, and chemical synthesis, J. Med. Chem. 2006, 49, 6931 6945; J. H. Liu, P. C. Smith, Predicting the pharmacokinetics of acyl glucuronides and their parent compounds in disease states, Curr. Drug Metab. 2006, 7, 147 163; A. V. Stachulski, The chemistry and biological activity of acyl glucuronides, Curr. Opin. Drug Discovery Dev. 2007, 10, 58 66. C. Li, L. Z. Benet, M. P. Grillo, Studies on the chemical reactivity of 2-phenylproprionic acid 1-Oacyl glucuronide and S-acyl-CoA thioester metabolites, Chem. Res. Toxicol. 2002, 15, 1309 1317; M. P. Grillo, C. G. Knutson, P. E. Sanders, D. J. Waldon, F. Hua, J. A. Ware, Studies on the chemical reactivity of diclofenac acyl glucuronide with glutathione: identification of diclofenac-S-acylglutathione in rat bile, Drug Metab. Dispos. 2003, 31, 1327 1336. a) M. Iwaki, T. Ogiso, S. Inagawa, K. Kakehi, In vitro regioselective stability of b-1-O- and 2-acyl glucuronides of naproxen and their covalent binding to human serum albumin, J. Pharm. Sci. 1999,
2317
[122]
[123]
[124]
[125]
[126]
[127] [128]
[129]
88, 52 57; b) K. A. McGurk, R. P. Remmel, V. P. Hosagrahara, D. Tosh, B. Burchell, Reactivity of mefenamic acid-1-O-acyl glucuronide with proteins in vitro and ex vivo, Drug Metab. Dispos. 1996, 24, 842 849. S. J. Vanderhoeven, J. C. Lindon, J. Troke, G. E. Tranter, I. D. Wilson, J. K. Nicholson, NMR and QSAR studies on the transacylation reactivity of model 1b-O-acyl glucuronides. I: Design, synthesis and degradation rate measurement, Xenobiotica 2004, 34, 73 85; E. Skordi, I. D. Wilson, J. C. Lindon, J. K. Nicholson, Kinetic studies on the intramolecular acyl migration of b-1-O-acyl glucuronides: application to the glucuronides of (R)- and (S)-ketoprofen, (R)- and (S)-hydroxyketoprofen metabolites, and tolmetin by 1H-NMR spectroscopy, Xenobiotica 2005, 35, 715 725; G. S. Walker, J. Atherton, J. Bauman, C. Kohl, W. Lam, M. Reily, Z. Lou, A. Mutlib, Determination of degradation pathways and kinetics of acyl glucuronides by NMR spectroscopy, Chem. Res. Toxicol. 2007, 20, 876 886; K. Akira, H. Hasegawa, Y. Shinohara, M. Imachi, T. Hashimoto, Stereoselective internal acyl migration of 1b-O-acyl glucuronides of enantiomeric 2-phenylpropionic acids, Biol. Pharm. Bull. 2000, 23, 506 510. a) J. Wang, M. Davis, F. li, F. Azam, J. Scatina, R. Talaat, A novel approach for predicting acyl glucuronide reactivity via Schiff base formation: development of rapidly formed peptide adducts for LC/MS/MS measurements, Chem. Res. Toxicol. 2004, 17, 1206 1216; b) A. Ding, J. C. Ojingwa, A. F. McDonagh, A. L. Burlingame, L. Z. Benet, Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry, Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 3797 3801; c) L. Z. Benet, H. Spahn-Langguth, S. Iwakawa, C. Volland, T. Mizuma, S. Mayer, E. Mutschler, E. T. Lin, Predictability of the covalent binding of acidic drugs in man, Life Sci. 1993, 53, 141 146. a) M. J. Bailey, R. G. Dickinson, Chemical and immunological comparison of protein adduct formation of four carboxylate drugs in rat liver and plasma, Chem. Res. Toxicol. 1996, 9, 659 666; b) B. C. Sallustio, B. A. Fairchild, P. R. Pannall, Interaction of human serum albumin with the electrophilic metabolite 1-O-gemfibrozil-b-d-glucuronide, Drug Metab. Dispos. 1997, 25, 55 60; c) N. Presle, F. Lapicque, S. Fournel-Gigleux, J. Magdalou, P. Netter, Stereoselective irreversible binding of ketoprofen glucuronides to albumin, Drug Metab. Dispos. 1996, 24, 1050 1057. B. C. Sallustio, Y. C. DeGraaf, J. S. Weekley, P. C. Burcham, Bioactivation of carboxylic acid compounds by UDP-glucuronosyltransferases to DNA-damaging intermediates: role of glycoxidation and oxidative stress in genotoxicity, Chem. Res. Toxicol. 2006, 19, 683 691; V. V. Mossine, M. Linetsky, G. V. Glinsky, B. J. Ortwert, M. S. Feather, Superoxide free radical generation by Amadori compounds: the role of acyclic forms and metal ions, Chem. Res. Toxicol. 1999, 12, 230 236. S. P. Wolff, R. T. Dean, Glucose autoxidation and protein modification. The potential role of autoxidative glycosylation in diabetes, Biochem. J. 1987, 245, 243 250; R. G. Khalifah, J. W. Baynes, B. G. Hudson, Amadorins: novel post-Amadori inhibitors of advanced glycation reactions, Biochem. Biophys. Res. Commun. 1999, 257, 251 258; J. W. Baynes, The Maillard hypothesis on aging: time to focus on DNA, Ann. N.Y. Acad. Sci. 2002, 959, 360 367; G. Aldini, I. Dalle-Donne, R. Maffei Facino, A. Milzani, M. Carini, Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls, Med. Res. Rev. 2007, 27, 817 868. B. A. Hamelin, J. Turgeon, Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors, Trends Pharmacol. Sci. 1998, 19, 26 37. T. Prueksaritanont, R. Sabramanian, X. Fang, B. Ma, Y. Qiu, J. H. Lin, P. G. Pearson, T. A. Baillie, Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization, Drug Metab. Dispos. 2002, 30, 505 512; H. Fujino, I. Yamada, S. Shimada, M. Yoneda, J. Kojima, Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: human UDP-glucuronosyltransferase enzymes involved in lactonization, Xenobiotica 2003, 33, 27 41. X. Meng, J. L. Maggs, D. C. Pryde, S. Planken, R. E. Jenkins, T. M. Peakman, K. Beaumont, C. Kohl, B. Kevin Park, A. V. Stachulski, Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide: synthesis, reactivity, and mechanistic analysis, J. Med. Chem. 2007, 50, 6165 6176.
2318
[130] C. Esser, Immunotoxicology, in ADME-Tox Approaches, Eds. B. Testa, H. van de Waterbeemd, Vol. 5 in Comprehensive Medicinal Chemistry, 2nd edn., Eds. J. B. Taylor, D. J. Triggle, Elsevier, Oxford, 2007, p. 215 229. [131] T. Ohkawa, R. Norikura, T. Yoshikawa, Rapid LC-TOFMS method for identification of binding sites of covalent acylglucuronides-albumin complexes, J. Pharm. Biomed. Anal. 2003, 31, 1167 1176. [132] B. C. Cupid, C. R. Beddell, J. C. Lindon, I. D. Wilson, J. K. Nicholson, QSAR for substituted benzoic acids in the rabbit: prediction of urinary excretion of glycine and glucuronide conjugates, Xenobiotica 1996, 26, 157 176. [133] K. Akira, T. Uchijima, T. Hashimoto, Rapid internal acyl migration and protein binding of synthetic probenecid glucuronides, Chem. Res. Toxicol. 2002, 15, 765 772. [134] P. Gaganis, J. O. Miners, K. M. Knights, Glucuronidation of fenamates: kinetic studies using human kidney cortical microsomes and recombinant UDP-glucuronosyltransferases (UGT) 1A9 and 2B7, Biochem. Pharmacol. 2007, 73, 1683 1691. [135] J. A. Watt, A. R. King, R. G. Dickinson, Contrasting systemic stabilities of the acyl and phenolic glucuronides of diflunisal in the rat, Xenobiotica 1991, 21, 403 415; A. R. King, R. G. Dickinson, Studies on the reactivity of acyl glucuronides. IV. Covalent binding of diflunisal to tissues of the rat, Biochem. Pharmacol. 1993, 45, 1043 1047. [136] G. E. Kuehl, J. Bigler, J. D. Potter, J. W. Lampe, Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes, Drug Metab. Dispos. 2006, 34, 199 202. [137] M. Katoh, T. Matsui, T. Yokoi, Glucuronidation of antiallergic drug, tranilast: identification of human UDP-glucuronosyltransferase isoforms and effect of its phase I metabolite, Drug Metab. Dispos. 2007, 35, 583 589. [138] P. J. Hayball, Formation and reactivity of acyl glucuronides: the influence of chirality, Chirality 1995, 7, 1 9. [139] K. Tougou, H. Gotou, Y. Ohno, A. Nakamura, Stereoselective glucuronidation and hydroxylation of etodolac by UGT1A9 and CYP2C9 in man, Xenobiotica 2004, 34, 449 461. [140] a) M. El Mouelhi, S. Beck, K. W. Bock, Stereoselective glucuronidation of (R)- and (S)-naproxen by recombinant rat phenol UDP-glucuronosyltransferase (UGT1A1) and its human orthologue, Biochem. Pharmacol. 1993, 46, 1298 1300; b) R. W. Mortensen, O. Corcoran, C. Cornett, U. G. Sidelmann, J. C. Lindon, J. K. Nicholson, S. H. Hansen, S-Naproxen-b-1-O-acyl glucuronide degradation kinetic studies by stopped-flow HPLC-1H NMR and HPLC-UV, Drug Metab. Dispos. 2001, 29, 375 380; c) O. Corcoran, R. W. Mortensen, S. H. Hansen, J. Troke, J. K. Nicholson, HPLC/1H NMR spectroscopic studies of the reactive a-1-O-acyl isomer formed during acyl migration of S-naproxen b-1-O-acyl glucuronide, Chem. Res. Toxicol. 2001, 14, 1363 1370. [141] Z. Wen, S. T. Stern, D. E. Martin, K.-H. Lee, P. S. Smith, Structural characterization of anti-HIV drug candidate PA-457 [3-O-(3,3-dimethylsuccinyl)-betulinic acid] and its acyl glucuronides in rat bile and evaluation of in vitro stability in human and animal liver microsomes and plasma, Drug Metab. Dispos. 2006, 34, 1436 1442. [142] S. H. Lee Chiu, S. W. Huskey, Species differences in N-glucuronidation, Drug Metab. Dispos. 1998, 26, 838 847. [143] A. G. Staines, M. W. H. Coughtrie, B. Burchell, N-Glucuronidation of carbamazepine in human tissues is mediated by UGT2B7, J. Pharmacol. Exp. Ther. 2004, 311, 1131 1137. [144] D. Zhang, W. Zhao, V. A. Roongta, J. G. Mitroka, L. J. Klunk, M. Zhu, Amide N-glucuronidation of MaxiPost catalyzed by UDP-glucuronosyltransferase 2B7 in humans, Drug Metab. Dispos. 2004, 32, 545 551. [145] J. J. Yuan, D.-C. Yang, J. Y. Zhang, R. Bible Jr., A. Karim, J. W. A. Findlay, Disposition of a specific cyclooxygenase-2 inhibitor, valdecoxib, in humans, Drug Metab. Dispos. 2002, 30, 1013 1021. [146] T. B. Vree, E. W. J. Beneken Kolmer, M. Martea, R. Bosch, Y. A. Hekster, M. Shimoda, Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in man, Pharm. Weekbld. Sci. Ed. 1990, 12, 51 59. [147] M. D. Green, T. R. Tephly, Glucuronidation of amine substrates by purified and expressed UDPglucuronosyltransferase proteins, Drug Metab. Dispos. 1998, 26, 860 867; M. D. Green, C. D. King,
2319
[148]
[149] [150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158] [159]
B. Mojarrabi, P. I. Mackensie, T. R. Tephly, Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3, Drug Metab. Dispos. 1998, 26, 507 512. T. V. Zenser, V. M. Lakshmi, B. B. Davis, N-Glucuronidation of benzidine and its metabolites, Drug Metab. Dispos. 1998, 26, 856 859; S. R. Babu, V. M. Lakshmi, I. S. Owens, T. V. Zenser, B. B. Davis, Human liver glucuronidation of benzidine, Carcinogenesis 1994, 15, 2003 2007; T. V. Zenser, V. M. Lakshmi, B. B. Davis, Human and Escherichia coli b-glucuronidase hydrolysis of glucuronide conjugates of benzidine and 4-aminobiphenyl, and their hydroxy metabolites, Drug Metab. Dispos. 1998, 26, 1064 1067; S. R. Babu, V. M. Lakshmi, G. P. Huang, T. V. Zenser, B. B. Davis, Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites. pH stability and synthesis by human and dog liver, Biochem. Pharmacol. 1996, 51, 1679 1685. B. Testa, The Metabolism of Drugs and Other Xenobiotics Biochemistry of Redox Reactions, Academic Press, London, 1995. W. F. Trager, Principles of drug metabolism 1: Redox reactions, in ADME-Tox Approaches, Eds. B. Testa, H. van de Waterbeemd, Vol. 5 in Comprehensive Medicinal Chemistry, 2nd edn., Eds. J. B. Taylor, D. J. Triggle, Elsevier, Oxford, 2007, p. 87 132. B. Oesch-Bartlomowicz, F. Oesch, Mechanisms of toxification and detoxification that challenge drug candidates and drugs, in ADME-Tox Approaches, Eds. B. Testa, H. van de Waterbeemd, Vol. 5 in Comprehensive Medicinal Chemistry, 2nd edn., Eds. J. B. Taylor, D. J. Triggle, Elsevier, Oxford, 2007, p. 193 214. A. E. Mutlib, W. L. Nelson, Synthesis and identification of the N-glucuronides of norgallopamil and norverapamil, unusual metabolites of gallopamil and verapamil, J. Pharmacol. Exp. Ther. 1990, 252, 593 599. P. J. McNelly, C. D. Torchin, L. W. Anderson, I. M. Kapetanovic, H. J. Kupferberg, J. M. Strong, In vitro glucuronidation of D-23129, a new anticoagulant, by human liver microsomes and liver slices, Xenobiotica 1997, 27, 431 441. H. Luo, E. M. Hawes, G. McKay, E. D. Korchinski, K. K. Midha, N -Glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans, Xenobiotica 1991, 21, 1281 1288; E. M. Hawes, N -Glucuronidation, a common pathway in the human metabolism of drugs with a tertiary amine group, Drug Metab. Dispos. 1998, 26, 830 837; U. Breyer-Pfaff, The metabolic fate of amitriptyline, nortriptyline and amitriptylineoxide in man, Drug Metab. Rev. 2004, 36, 723 746. T. Kaku, K. Ogura, T. Nishiyama, T. Ohnuma, K. Muro, A. Hiratsuka, Quaternary ammoniumlinked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4, Biochem. Pharmacol. 2004, 67, 2093 2102; K. Ogura, Y. Ishikawa, T. Kaku, T. Nishiyama, T. Ohnuma, K. Muro, A. Hiratsuka, Quaternary ammonium-linked glucuronidation of trans-4hydroxytamoxifen, by human liver microsomes and UDP-glucuronosyltransferase 1A4, Biochem. Pharmacol. 2006, 71, 1358 1369. U. Breyer-Pfaff, Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine, Drug Metab. Dispos. 2001, 29, 1343 1348; H. Luo, E. M. Hawes, G. McKay, E. D. Korchinski, K. K. Midha, The quaternary ammonium-linked glucuronide of doxepin: a major metabolite in depressed patients treated with doxepin, Drug Metab. Dispos. 1991, 19, 722 724. G. E. Kuehl, S. E. Murphy, N-Glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases, Drug Metab. Dispos. 2003, 31, 1361 1368; O. Ghosheh, E. M. Hawes, Microsomal N-glucuronidation of nicotine and cotinine: human hepatic interindividual, human intertissue, and interspecies hepatic variation, Drug Metab. Dispos. 2002, 30, 1478 1483; N. L. Benowitz, E. J. Perez-Stable, I. Fong, G. modin, B. Herrera, P. Jacob III, Ethnic differences in N-glucuronidation of nicotine and cotinine, J. Pharmacol. Exp. Ther. 1999, 291, 1196 1203. J. H. Lin, Role of pharmacokinetics in the discovery and development of indinavir, Adv. Drug Delivery Rev. 1999, 39, 33 49. D. Wiener, D. R. Doerge, J.-L. Fang, P. Upadhyaya, P. Lazarus, Characterization of Nglucuronidation of the lung carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL)
2320
[160] [161]
[162]
[163]
[164]
[165] [166]
[167]
[168]
[169] [170] [171] [172]
in human liver: importance of UDP-glucuronosyltransferase 1A4, Drug Metab. Dispos. 2004, 32, 72 79; S. G. Carmella, K. Le, P. Upadhyaya, S. S. Hecht, Analysis of N- and O-glucuronides of 4(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL) in human urine, Chem. Res. Toxicol. 2002, 15, 545 550; Q. Ren, S. E. Murphy, A. J. Dannenberg, J. Y. Park, T. R. Tephly, P. Lazarus, Glucuronidation of the lung carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL) in rat UDP-glucuronosyltransferase 2B1, Drug Metab. Dispos. 1999, 27, 1010 1016. P. V. Macrae, M. Kinns, F. S. Pullen, M. H. Tarbit, Characterization of a quaternary, N-glucuronide metabolite of the imidazole antifungal, tioconazole, Drug Metab. Dispos. 1990, 18, 1100 1102. S. C. Vashishtha, E. M. Hawes, G. McKay, D. J. McCann, Quaternary ammonium-linked glucuronidation of 1-substituted imidazoles: studies of human UDP-glucuronosyltransferases involved and substrate specificities, Drug Metab. Dispos. 2001, 29, 1290 1295; S. C. Vashishtha, E. M. Hawes, D. J. McCann, O. Ghosheh, L. Hogg, Quaternary ammonium-linked glucuronidation of 1-substituted imidazoles by liver microsomes: interspecies differences and structure-metabolism relationships, Drug Metab. Dispos. 2002, 30, 1070 1076. S.-H. W. Huskey, R. R. Miller, S.-H. Lee Chiu, N-Glucuronidation reactions. I. Tetrazole Nglucuronidation of selected angiotensin II receptor antagonists in hepatic microsomes from rats, dogs, monkeys and humans, Drug Metab. Dispos. 1993, 21, 792 799; S.-H. W. Huskey, G. A. Doss, R. R. Miller, W. R. Schoen, S.-H. Lee Chiu, N-Glucuronidation reactions. II. Relative Nglucuronidation reactivity of methylbiphenyl tetrazole, methylbiphenyl triazole, and methylphenyl imidazole in rat, monkey, and human microsomes, Drug Metab. Dispos. 1994, 22, 651 658. Z. Yan, G. W. Caldwell, D. Gauthier, G. C. Leon, J. Mei, C. Y. Ho, W. J. Jones, J. A. Masucci, R. W. Tuman, R. A. Galemmo Jr., D. L. Johnson, N-Glucuronidation of the platelet-derived growth factor receptor tyrosine kinase inhibitor 6,7-(dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)-(3fluorophenyl)-amine by human UDP-glucuronosyltransferases, Drug Metab. Dispos. 2006, 34, 748 755. A. Rowland, D. J. Elliot, J. A. Williams, P. I. Mackenzie, R. G. Dickinson, J. O. Miners, In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction, Drug Metab. Dispos. 2006, 34, 1055 1062; W. Lu, J. P. Uetrecht, Possible bioactivation pathways of lamotrigine, Drug Metab. Dispos. 2007, 35, 1050 1056. M. Nakaoka, Kinetic characteristics of UGT-glucuronosyltransferases towards a dithiol metabolite of malotilate in hepatic microsomes of rats and rabbits, Xenobiotica 1990, 20, 619 627. K. A. Keating, O. McConnell, Y. Zhang, L. Shen, W. DeMaio, L. Mallis, S. Elmarakby, A. Chandrasekaran, NMR characterization of an S-linked glucuronide metabolite of the potent, novel, nonsteroidal progesterone agonist tanaproget, Drug Metab. Dispos. 2006, 34, 1283 1287. O. Kerdpin, D. J. Elliot, P. I. Mackenzie, J. O. Miners, Sulfinpyrazone C-glucuronidation is catalyzed selectively by human UGT-glucuronosyltransferase 1A9, Drug Metab. Dispos. 2006, 34, 1950 1954; W. Dieterle, J. W. Faigle, H. Mory, W. J. Richter, W. Theobald, Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan) in man, Eur. J. Clin. Pharmacol. 1975, 9, 135 145; C. R. Abolin, T. N. Tozer, J. C. Craig, L. D. Gruenke, C-Glucuronidation of the acetylenic moiety of ethchlorvynol in the rabbit, Science 1980, 209, 703 704. G. Genchi, W. Wang, A. Barua, W. R. Bidlack, J. A. Olson, Formation of b-glucuronides and of bgalacturonides of various retinoids catalyzed by induced and noninduced microsomal UDPglucuronosyltransferases of rat liver, Biochim. Biophys. Acta 1996, 1289, 284 290. H. Kamimura, H. Ogata, H. Takahara, a-Glucoside formation of xenobiotics by rat liver aglucosidases, Drug Metab. Dispos. 1992, 20, 309 315. G. D. Paulson, V. J. Feil, J. M. Giddings, C. H. Lamoureux, Lactose conjugation of sulphonamide drugs in the lactating dairy cow, Xenobiotica 1992, 22, 925 939. H. Major, J. Castro-Perez, J. K. Nicholson, I. D. Wilson, Detection of mono- and di-hexoses as metabolites of 4-bromoaniline using HPLC-TOF-MS/MS, Xenobiotica 2003, 33, 855 869. M. Shipkova, V. W. Armstrong, E. Wieland, P. D. Niedmann, E. Schtz, G. Brenner-Weiss, M. Voihsel, F. Braun, M. Oellerich, Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil, Br. J. Pharmacol. 1999, 126, 1075 1082; M. Shipkova, C. P. Strassburg, F. Braun, F. Streit,
2321
[173] [174] [175] [176]
[177]
[178] [179]
[180]
[181] [182]
[183]
[184]
H.-J. Grne, V. W. Armstrong, R. H. Tukey, M. Oellerich, E. Wieland, Glucuronide and glucoside conjugation of mycophenolic acid in plasma by human liver, kidney and intestinal microsomes, Br. J. Pharmacol. 2001, 132, 1027 1034; Y. Uwai, H. Motohashi, Y. Tsuji, H. Ueo, T. Katsura, K. Inui, Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3, Biochem. Pharmacol. 2007, 74, 161 168. E. Samara, M. Bialer, D. J. Harvey, Identification of glucose conjugates as major urinary metabolites of cannabidiol in the dog, Xenobiotica 1990, 20, 177 183. B. Egestad, P. Sjberg, Glucosidation as a new conjugation pathway for metabolites of bis(2ethylhexyl) phthalate, Drug Metab. Dispos. 1992, 20, 470 472. D. E. Duggan, J. J. Baldwin, B. H. Arison, R. E. Rhodes, N-Glucoside formation as a detoxification mechanism in mammals, J. Pharmacol. Exp. Ther. 1974, 190, 563 569. W. H. Soine, P. J. Soine, S. E. Mongrain, T. M. England, Stereochemical characterization of the diastereomers of the phenobarbital N-b-d-glucose conjugate excreted in human urine, Pharm. Res. 1990, 7, 402 406; S. M. Neighbors, W. H. Soine, Identification of phenobarbital N-glucuronides as urinary metabolites of phenobarbital in mice, Drug Metab. Dispos. 1995, 23, 548 552. W. H. Soine, P. J. Soine, F. C. Wireko, D. J. Abraham, Stereochemical characterization of the diastereomers of the amobarbital N-glucosides excreted in human urine, Pharm. Res. 1990, 7, 794 800; W. H. Soine, P. J. Soine, T. M. England, R. M. Graham, G. Capps, Identification of the diastereomers of pentobarbital N-glucosides excreted in human urine, Pharm. Res. 1994, 11, 1535 1539; W. H. Soine, C.-F. Yu, D. Thomas, S. L. Cao, R. B. Westkaemper, T. D. Williams, NGlucosylation of phenobarbital analogs by mouse liver microsomes, Med. Chem. Res. 1996, 6, 174 189. B. Testa, Principles of Organic Stereochemistry, Dekker, New York, 1979. K. Toide, Y. Terauchi, T. Fujii, H. Yamazaki, T. Kamataki, Uridine diphosphate sugar-selective conjugation of an aldose reductase inhibitor (AS-3201) by UDP-glucuronosyltransferase 2B subfamily in human liver microsomes, Biochem. Pharmacol. 2004, 67, 1269 1278; M. Kurono, A. Itogawa, H. Noguchi, M. Sanjoba, Stability and hydrolysis kinetics of spirosuccinimide type inhibitors of aldose reductase in aqueous solution and retardation of their hydrolysis by the target enzyme, J. Pharm. Sci. 2008, 97, 1468 1483. T. Nakazawa, K. Miyata, K. Omura, T. Iwanaga, O. Nagata, Metabolic profile of FYX-051 (4-(5pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and humans: identification of N-glucuronides and N-glucosides, Drug Metab. Dispos. 2006, 34, 1880 1886. J. Tjrnelund, S. H. Hansen, C. Cornett, New metabolites of the drug 5-aminosalicylic acid: N-b-dglucopyranosyl-5-aminosalicylic acid, Xenobiotica 1989, 19, 891 899. A. Kawamura, J. Graham, A. Mushtaq, S. A. Tsiftsoglou, G. M. Vath, P. E. Hanna, C. R. Wagner, E. Sim, Eukaryotic arylamine N-acetyltransferase. Investigation of substrate specificity by highthroughput screening, Biochem. Pharmacol. 2002, 69, 347 359; S. Boukouvala, G. Fakis, Arylamine N-acetyltransferases: what we learn from genes and genomes, Drug Metab. Rev. 2005, 37, 511 564; J. M. Walraven, J. O. Trent, D. W. Hein, Computational and experimental analyses of mammalian arylamine N-acetyltransferase structure and function, Drug Metab. Dispos. 2007, 35, 1001 1007; L. Liu, A. Von Vett, N. Zjang, K. J. Walters, C. R. Wagner, P. E. Hanna, Arylamine N-acetyltransferases: characterization of the substrate specificities and molecular interactions of environmental arylamines with human NAT1 and NAT2, Chem. Res. Toxicol. 2007, 20, 1300 1308; D. A. Price-Evans, N-Acetyltransferase, Pharmacol. Ther. 1989, 42, 157 234. a) L. W. Wormhoudt, J. N. Commandeur, N. P. Vermeulen, Genetic polymorphisms of human Nacetyltransferase, cytochrome P450, glutathione S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity, Crit. Rev. Toxicol. 1999, 29, 59 124; b) D. M. Grant, N. C. Hughes, S. A. Janezic, G. H. Goodfellow, H. J. Chen, A. Gaedigk, V. L. Yu, R. Grewal, Human acetyltransferase polymorphism, Mutat. Res. 1997, 376, 61 70; c) C. Bruhn, J. Brockmller, I. Cascorbi, I. Roots, H.-H. Borchert, Correlation between genotype and phenotype of the human arylamine N-acetyltransferase type I (NAT1), Biochem. Pharmacol. 1999, 58, 1759 1764. D. W. Hein, D. M. Grant, E. Sim, Update on consensus arylamine N-acetyltransferase gene nomenclature, Pharmacogenetics 2000, 10, 291 292 (http://louisville.edu/medschool/pharmacology/NAT.html); K. P. Vatsis, W. W. Weber, D. A. Bell, J.-M. Dupret, D. A. Price-Evans, D. M.
2322
[185]
[186]
[187]
[188]
[189]
[190]
[191]
[192]
[193] [194]
[195] [196]
Grant, D. W. Hein, H. J. Lin, U. A. Meyer, M. V. Relling, E. Sim, T. Suzuki, Y. Yamazoe, Nomenclature for N-acetyltransferases, Pharmacogenetics 1995, 5, 1 17. J. C. Sinclair, J. Sandy, R. Delgoda, E. Sim, M. E. M. Noble, Structure of arylamine Nacetyltransferase reveals a catalytic triad, Nat. Struct. Biol. 2000, 7, 560 564; H. Wu, L. Dombrovsky, W. Tempel, F. Martin, P. Loppnau, G. H. Goodfellow, D. M. Grant, A. N. Plotnikov, Structural basis of substrate-binding specificity of human arylamine N-acetyltransferase, J. Biol. Chem. 2007, 282, 30189 30197; Y. Hwang, P. R. Thompson, L. Wang, L. Jiang, N. L. Kelleher, P. A. Cole, A selective chemical probe for coenzyme A-requiring enzymes, Angew. Chem., Int. Ed. 2007, 46, 7621 7624. K. S. Sugamori, D. Brenneman, S. Wong, A. Gaedigk, V. Yu, H. Abramocivi, R. Rozmahel, D. M. Grant, Effect of arylamine acetyltransferase Nat3 gene knockout on N-acetylation in the mouse, Drug Metab. Dispos. 2007, 35, 1064 1070; L. Estrada-Rodgers, G. N. Levy, W. W. Weber, Substrate selectivity of mouse N-acetyltransferases 1, 2, and 3 expressed in COS-1 cells, Drug Metab. Dispos. 1997, 26, 502 505. T. B. Vree, E. W. J. Beneken Kolmer, Y. A. Hekster, M. Shimoda, M. Ono, T. Miura, Pharmacokinetics, N1-glucuronidation, and N4-acetylation of sulfa-6-monomethoxine in humans, Drug Metab. Dispos. 1990, 18, 852 858. W. Gao, J. S. Johnston, D. D. Miller, J. T. Dalton, Interspecies differences in pharmacokinetics and metabolism of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)-propionamide: the role of N-acetyltransferase, Drug Metab. Dispos. 2006, 34, 254 260. S. Antila, U. Pesonen, L. Lehtonen, P. Tapanainen, H. Nikkanen, K. Vaahtera, H. Scheinin, Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators, Eur. J. Pharm. Sci. 2004, 23, 213 222; M. Koskinen, J. Puttonen, M. Pyklinen, A. Vuorela, T. Lotta, Metabolism of OR-1896, a metabolite of levosimendan, in rats and humans, Xenobiotica 2008, 38, 156 170. L. E. Lemke, C. A. McQueen, Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine, Drug Metab. Dispos. 1995, 23, 559 565; V. Facchini, J. A. Timbrell, Further evidence for an acetylator phenotype difference in the metabolism of hydralazine in man, Br. J. Clin. Pharmacol. 1981, 11, 345 351. P. Preziosi, Isoniazid: metabolic aspects and toxicological correlates, Curr. Drug Metab. 2007, 8, 839 851; R. Kubota, M. Ohno, T. Hasunuma, H. Iijima, J. Azuma, Dose-escalation study of isoniazid in healthy volunteers with the rapid acetylator genotype of arylamine N-acetyltransferase 2, Eur. J. Clin. Pharmacol. 2007, 63, 927 933; P. R. Donald, D. P. Parkin, H. I. Seifart, H. S. Schaaf, P. D. van Heiden, C. J. Werely, F. A. Sirgel, A. Venter, J. S. Maritz, The influence of dose and Nacetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid, Eur. J. Clin. Pharmacol. 2007, 63, 633 639. B. H. Lauterburg, C. V. Smith, J. R. Mitchell, Determination of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine, and diacetylhydrazine in human plasma by GC-MC, J. Chromatogr. 1981, 224, 431 438; Y. S. Huang, H. D. Chen, W. J. Su, J. C. Wu, S. L. Lai, S. Y. Yang, F. Y. Chang, S. D. Lee, Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis, Hepatology 2002, 35, 883 889. A. Noda, Y. Ono, X. Wu, K. Kudo, N. Jitsufuchi, S. Eto, H. Noda, Determination and properties of acetyl conjugate of N-desisopropylpropranolol, AcNDP, Biol. Pharm. Bull. 1995, 18, 1454 1455. I. Ieiri, T. Morioka, S. Kim, S. Nishio, M. Fukui, S. Higuchi, Pharmacokinetic study of zonisamide in patients undergoing brain surgery, J. Pharm. Pharmacol. 1996, 48, 1270 1275; D. D. Stiff, M. A. Zemaitis, Metabolism of the anticonvulsant agent zonisamide in the rat, Drug Metab. Dispos. 1990, 18, 888 894; I. E. Leppik, Zonisamide: chemistry, mechanism of action, and pharmacokinetics, Seizure 2004, 13 (Suppl. 1), S5 S10. F. N. Shirota, H. T. Nagasawa, C. H. Kwon, E. G. Demaster, N-Acetylcyanamide, the major urinary metabolite of cyanamide in rat, rabbit, dog, and man, Drug Metab. Dispos. 1984, 12, 337 344. K. S. Sugamori, D. Brennerman, D. M. Grant, In vivo and in vitro metabolism of arylamine procarcinogens in acetyltransferase-deficient mice, Drug Metab. Dispos. 2006, 34, 1697 1702; N. Carreon, A. M. Ruder, P. A. Schulte, R. B. Hayes, N. Rothman, M. Waters, D. J. Grant, R. Boissy,
2323
[197]
[198]
[199]
[200] [201]
[202]
[203]
[204]
[205]
[206]
D. A. Bell, F. F. Kadlubar, G. P. Hemstreet III, S. Yin, G. K. LeMasters, NAT2 slow acetylation and bladder cancer in workers exposed to benzidine, Int. J. Cancer 2006, 118, 161 168; V. M. Lakshmi, T. V. Zenser, H. D. Goldman, G. G. Spencer, R. C. Gupta, F. F. Hsu, B. B. Davis, The role of acetylation in benzidine metabolism and DNA adduct formation in dog and rat liver, Chem. Res. Toxicol. 1995, 8, 711 720. P. D. Josephy, D. H. Evans, A. Parikh, F. P. Guengerich, Metabolic activation of aromatic amine mutagens by simultaneous expression of human cytochrome P450 1A2, NADPH-cytochrome P450 reductase, and N-acetyltransferase in E. coli, Chem. Res. Toxicol. 1998, 11, 70 74; D. W. Hein, M. A. Doll, K. Gray, T. D. Rustan, R. J. Ferguson, Metabolic activation of N-hydroxy-2aminofluorene and N-hydroxy-2-acetylaminofluorene by monomorphic N-acetyltransferase (NAT1) and polymorphic N-acetyltransferase (NAT2) in colon cytosols of Syrian hamsters congenic at the NAT2 locus, Cancer Res. 1993, 53, 509 514. L. W. Boteju, P. E. Hanna, Arylamine-nucleoside adduct formation: evidence for arylnitrene involvement in the reactions of an N-acetoxyarylamine, Chem. Res. Toxicol. 1994, 7, 684 689; G. L. Borosky, Ultimate carcinogenic metabolites from aromatic and heterocyclic aromatic amine: a computational study in relation to their mutagenic potency, Chem. Res. Toxicol. 2007, 20, 171 180; E. Y. Lau, J. S. Felton, F. C. Lightstone, Insights into the O-acetylation reaction of hydroxylated heterocyclic amines by human N-acetyltransferases: a computational study, Chem. Res. Toxicol. 2006, 19, 1182 1190. H. Wang, C. R. Wagner, P. E. Hanna, Irreversible inactivation of arylkamine N-acetyltransferases in the presence of N-hydroxy-4-acetylaminobiphenyl: a comparison of human and hamster enzymes, Chem. Res. Toxicol. 2005, 18, 183 197; L. W. Boteju, P. E. Hanna, Bioactivation of Nhydroxy-2-acetylaminofluorenes by N,O-acyltransferase: substituent effects on covalent binding to DNA, Carcinogenesis 1993, 14, 1651 1657; K. Saito, A. Shinohara, T. Kamataki, R. Kato, NHydroxyarylamine O-acetyltransferase in hamster liver: identity with arylhydroxamic acid N,Oacetyltransferase and arylamine N-acetyltransferase, J. Biochem. 1986, 99, 1689 1697. G. A. S. Ansari, B. S. Kaphalia, M. F. Khan, Fatty acid conjugates of xenobiotics, Toxicol. Lett. 1995, 75, 1 17. K. F. Buhman, M. Accad, R. V. Farese, Mammalian acyl-CoA : cholesterol acyltransferases, Biochim. Biophys. Acta 2000, 1529, 142 154; R. B. Hochberg, Biological esterification of steroids, Endocr. Rev. 1998, 19, 331 348; S. L. Pahija, R. B. Hochberg, A comparison of the esterification of steroids by rat lecithin : cholesterol acyltransferase and acyl coenzyme A : cholesterol acyltransferase, Endocrinology 1995, 136, 180 186. S. Xu, B. T. Zhu, A. H. Conney, Stimulatory effect of clofibrate and gemfibrozil administration on the formation of fatty acid esters of estradiol by rat liver microsomes, J. Pharmacol. Exp. Ther. 2001, 296, 188 197. M. Jendbro, C.-J. Johansson, P. Strandberg, H. Falk-Nilsson, S. Edsbcker, Pharmacokinetics of budesonide and its major ester metabolite after inhalation and intravenous administration of budesonide in the rat, Drug Metab. Dispos. 2001, 29, 769 776; A. Miller-Larsson, H. Mattsson, E. Hjertberg, M. Dahlbck, A. Tunek, R. Brattsand, Reversible fatty acid conjugation of budesonide, Drug Metab. Dispos. 1998, 26, 623 630; A. Tunek, K. Sjdin, G. Hallstrm, Reversible formation of fatty acid esters of budesonide, an antiasthma glucocorticoid, in human lung and liver microsomes, Drug Metab. Dispos. 1997, 25, 1311 1317. P. F. Dodds, Xenobiotic lipids: the inclusion of xenobiotic compounds in pathways of lipid biosynthesis, Prog. Lipid Res. 1995, 34, 219 247; J. Caldwell, M. Varwell Marsh, Interrelationships between xenobiotic metabolism and lipid biosynthesis, Biochem. Pharmacol. 1983, 32, 1667 1672; J. Caldwell, B. G. Lake, Eds., Inter-relationships between xenobiotic metabolism and lipid biochemistry, Biochem. Soc. Trans. 1985, 861, 847 862. R. Leonardi, Y.-M. Zhang, C. O. Rock, S. Jackowski, Coenzyme A: back in action, Prog. Lipid Res. 2005, 44, 125 153; E. P. Brass, Overview of coenzyme A metabolism and its role in cellular toxicity, Chem.-Biol. Interact. 1994, 90, 203 214. K. M. Knights, C. J. Drogemuller, Xenobiotic-CoA ligases: Kinetic and molecular characterization, Curr. Drug Metab. 2000, 1, 49 66; K. M. Knights, Role of hepatic fatty acid : coenzyme A
2324
[207]
[208] [209]
[210]
[211]
[212]
[213]
[214]
[215]
[216] [217] [218]
ligases in the metabolism of xenobiotic carboxylic acids, Clin. Exp. Pharmacol. Physiol. 1998, 25, 776 782; F. Kasuya, Y. Yamaoka, K. Igarashi, M. Fukui, Molecular specificity of a medium chain acyl-CoA synthetase for substrates and inhibitors, Biochem. Pharmacol. 1998, 55, 1769 1775. C. J. Drogemuller, S. Nunthasomboon, K. M. Knights, Nafenopin-, ciprofibroyl-, and palmitoylCoA conjugation in vitro: kinetic and molecular characterization of marmoset liver microsomes and expressed MLCL1, Arch. Biochem. Biophys. 2001, 396, 56 64; C. J. Masters, On the role of the peroxisome in the metabolism of drugs and xenobiotics, Biochem. Pharmacol. 1998, 56, 667 673; B. J. Roberts, J. K. MacLeod, I. Singh, K. M. Knights, Kinetic characterization of rat liver peroxisomal nafenopin-CoA ligase, Biochem. Pharmacol. 1995, 49, 1335 1339. K. Waku, Origins and fates of fatty acyl-CoA esters, Biochim. Biophys. Acta 1992, 1124, 101 111. a) U. Sidenius, C. Skonberg, J. Olsen, S. H. Hansen, In vitro reactivity of carboxylic acid-CoA thioesters with glutathione, Chem. Res. Toxicol. 2004, 17, 75 81; b) R. Hilal, A. M. El-Aaser, A comparative quantum-chemical study of methyl acetate and S-methyl thioacetate. Toward an understanding of the biochemical reactivity of esters of coenzyme A, Biophys. Chem. 1985, 22, 145 150. M. C. Hunt, J. Yamada, L. J. Maltais, M. W. Wright, E. J. Podesta, S. E. H. Alexson, A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases, J. Lipid Res. 2005, 46, 2029 2032; J. Yamada, Long-chain acyl-CoA hydrolase in the brain, Amino Acids 2005, 28, 273 278; M. C. Hunt, K. Solaas, B. F. Kase, S. E. Alexson, Characterization of an acyl-CoA thioesterase that functions as a major regulator of peroxisomal lipid metabolism, J. Biol. Chem. 2002, 277, 1128 1138. a) J. Olsen, C. Li, C. Skonberg, I. Bjrnsdottir, U. Sidenius, L. Z. Benet, S. H. Hansen, Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats, Drug Metab. Dispos. 2007, 35, 758 764; b) J. Olsen, C. Li, I. Bjrnsdottir, U. Sidenius, S. H. Hansen, L. Z. Benet, In vitro and in vivo studies on acyl-coenzyme A-dependent bioactivation of zomepirac in rats, Chem. Res. Toxicol. 2005, 18, 1729 1736. B. Sallustio, S. Nunthasomboon, C. J. Drogemuller, K. M. Knights, In vitro covalent binding of nafenopin-CoA to human liver proteins, Toxicol. Appl. Pharmacol. 2002, 163, 176 182; C. Li, L. Z. Benet, M. P. Grillo, Enantioselective binding of 2-phenylpropionic acid to protein in vitro in rat hepatocytes, Chem. Res. Toxicol. 2002, 15, 1480 1487. N. Levoin, C. Blondeau, C. Guillaume, L. Grandcolas, F. Chretien, J.-Y. Jouzeau, E. Benoit, Y. Chapleur, P. Netter, F. Lapicque, Elucidation of the mechanism of inhibition of cyclooxygenases by acyl-CoA and acyl glucuronide conjugates of ketoprofen, Biochem. Pharmacol. 2004, 68, 1957 1969; W. Neupert, R. Brugger, C. Euchenhofer, K. Brune, G. Geisslinger, Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases, Br. J. Pharmacol. 1997, 122, 487 492. C. Kemal, J. E. Cassida, Coenzyme A esters of 2-aryloxyphenoxypropionate herbicides and 2arylpropionate antiinflammatory drugs are potent and stereoselective inhibitors of rat liver acetylCoA carboxylase, Life Sci. 1992, 50, 533 540; M. Bronfman, L. Amigo, M. N. Morales, Activation of hypolipidaemic drugs to acyl-CoA thioesters, Biochem. J. 1986, 239, 781 784. J. M. Mayer, M. Roy-de Vos, C. Audergon, B. Testa, J. Cl. Etter, Interactions of anti-inflammatory 2-arylpropionates (profens) with the metabolism of fatty acids in vitro studies, Int. J. Tissue React. 1994, 16, 59 72; K. M. Knights, R. Drew, The effects of ibuprofen enantiomers on hepatocyte intermediary metabolism and mitochondrial respiration, Biochem. Pharmacol. 1992, 44, 1291 1296; E. Freneaux, B. Fromenty, A. Berson, G. Labbe, C. Degott, P. Letteron, D. Larrey, D. Pessayre, Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial b-oxidation of fatty acids, J. Pharmacol. Exp. Ther. 1990, 255, 529 535. K. M. Knights, M. J. Sykes, J. O. Miners, Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids, Expert Opin. Drug Metab. Toxicol. 2007, 3, 159 168. G. C. Tremblay, I. A. Qureshi, The biochemistry and toxicology of benzoic acid metabolism and its relationship to the elimination of waste nitrogen, Pharmacol. Ther. 1993, 60, 63 90. A. J. Hutt, J. Caldwell, Amino acid conjugation, in Conjugation Reactions in Drug Metabolism, Ed. G. J. Mulder, Taylor & Francis, London, 1990, p. 273 305.
2325
[219] T. Nanbo, The electronic effects of benzoic acid substituents on glycine conjugation, Biol. Pharm. Bull. 1994, 17, 551 553; F. Kasuya, K. Igarashi, M. Fukui, Participation of a medium chain acylCoA synthetase in glycine conjugation of the benzoic acid derivatives with the electron-donating groups, Biochem. Pharmacol. 1996, 51, 805 809; T. Kanazu, T. Yamaguchi, Comparison of in vitro carnitine and glycine conjugation with branched-side chain and cyclic side chain carboxylic acids in rats, Drug Metab. Dispos. 1997, 25, 149 153. [220] B. C. Cupid, E. Holmes, I. D. Wilson, J. C. Lindon, J. K. Nicholson, Quantitative structuremetabolism relationships (QSMR) using computational chemistry: pattern recognition analysis and statistical prediction of phase II conjugation reactions of substituted benzoic acids in the rat, Xenobiotica 1999, 29, 27 42; T. Masuda, K. Nakamura, T. Jikihara, F. Kasuya, K. Igarashi, M. Fukui, T. Takagi, H. Fujiwara, 3D-Quantitative structure-activity relationships for hydrophobic interactions. Comparative molecular field analysis (CoMFA) including molecular lipophilicity potentials as applied to the glycine conjugation of aromatic as well as aliphatic carboxylic acids, Quant. Struct.-Act. Relat. 1996, 15, 194 200. [221] M. Iwaki, T. Ogiso, H. Hayashi, T. Tanino, L. Z. Benet, Acute dose-dependent disposition studies of nicotinic acid in rats, Drug Metab. Dispos. 1996, 24, 773 779. [222] A. J. Hutt, J. Caldwell, R. L. Smith, The metabolism of aspirin in man: a population study, Xenobiotica 1986, 16, 239 249; D. K. Patel, L. J. Notarianni, P. N. Bennett, Comparative metabolism of high doses of aspirin in man and rat, Xenobiotica 1990, 20, 847 854. [223] T. Kasumov, L. L. Brunengraber, B. Comte, M. A. Puchowicz, K. Jobbins, K. Thomas, F. David, R. Kinman, S. Wehrli, W. Dahms, D. Kerr, I. Nissim, H. Brunengraber, New secondary metabolites of phenylbutyrate in humans and rats, Drug Metab. Dispos. 2004, 32, 10 19. [224] V. S. Gopaul, W. Tang, K. Farrell, F. S. Abbott, Amino acid conjugates: metabolites of 2propylpentanoic acid (valproic acid) in epileptic patients, Drug Metab. Dispos. 2003, 31, 114 121. [225] C. N. Falany, M. R. Johnson, S. Barnes, R. B. Diasio, Glycine and taurine conjugation of bile acids by a single enzyme, J. Biol. Chem. 1994, 269, 19375 19379. [226] G. J. Lappin, T. D. Hardwick, R. Stow, G. H. Pigott, B. van Ravenzwaay, Absorption, metabolism and excreation of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog, Xenobiotica 2002, 32, 153 163. [227] a) M.-S. Kim, Z. Shen, C. Kochansky, K. Lynn, S. Wang, Z. Wang, D. Hora, J. Brunner, R. B. Franklin, S. H. Vincent, Differences in the metabolism and pharmacokinetics of two structurally similar PPAR agonists in dogs: involvement of taurine conjugation, Xenobiotica 2004, 34, 665 674; b) M. A. Shirley, P. Wheelan, S. R. Howell, R. C. Murphy, Oxidative metabolism of a rexinoid and rapid phase II metabolite identification by mass spectrometry, Drug Metab. Dispos. 1997, 25, 1144 1149. [228] M. A. Shirley, X. Guan, D. G. Kaiser, G. W. Halstead, T. A. Baillie, Taurine conjugation of ibuprofen in humans and in rat liver in vitro. Relationship to metabolic chiral inversion, J. Pharmacol. Exp. Ther. 1994, 269, 1166 1175; K. Mohri, K. Okada, L. Z. Benet, Stereoselective taurine conjugation of (R)-benoxaprofen enantiomer in rats: in vivo and in vitro studies using rat hepatic mitochondria, Pharm. Res. 2005, 22, 79 85. [229] P. F. Dodds, Incorporation of xenobiotic carboxylic acids into lipids, Life Sci. 1991, 49, 629 649; R. Fears, Lipophilic xenobiotic conjugates: the pharmacological and toxicological consequences of the participation of drugs and other foreign compounds as substrates in lipid biosynthesis, Prog. Lipid Res. 1986, 24, 177 195. [230] S. Vickery, P. F. Dodds, Incorporation of xenobiotic carboxylic acids into lipids by cultured 3T3-L1 adipocytes, Xenobiotica 2004, 34, 1025 1042; K. G. Moorhouse, P. F. Dodds, D. H. Hutson, Xenobiotic triacylglycerol formations in isolated hepatocytes, Biochem. Pharmacol. 1991, 41, 1179 1185. [231] a) A. Carabaza, N. Suesa, D. Tost, J. Pascual, M. Gomez, M. Gutierrez, E. Ortega, X. Montserrat, A. M. Garcia, R. Mis, F. Vabre, D. Mauleon, G. Carganico, Stereoselective metabolic pathways of ketoprofen in the rat: incorporation into triacylglycerols and enantiomeric inversion, Chirality 1996, 8, 163 172; b) K. Williams, R. Day, R. Knihinicki, A. Duffield, The stereoselective uptake of ibuprofen enantiomers into adipose tissue, Biochem. Pharmacol. 1986, 35, 3403 3405.
2326
[232] G. B. Quistad, L. E. Staiger, D. A. Schooley, Xenobiotic conjugation: a novel role for bile acids, Nature 1982, 296, 462 464. [233] A. Siafaka-Kapadai, M. Patiris, C. Bowden, M. Javors, Incorporation of [ 3H]valproic acid into lipids in GT1-7 neurons, Biochem. Pharmacol. 1998, 56, 207 212. [234] E. L. Sun, K. L. Feenstra, F. P. Bell, P. E. Sanders, J. G. Slatter, R. G. Ulrich, Biotransformation of lifibrol (U-83860) to mixed glyceride metabolites by rat and human hepatocytes in primary culture, Drug Metab. Dispos. 1996, 24, 221 231. [235] R. Fears, K. H. Baggaley, P. Walker, R. M. Hindley, Xenobiotic cholesteryl ester formation, Xenobiotica 1982, 12, 427 433. [236] H. Kaneko, M. Matsuo, J. Miyamoto, Differential metabolism of fenvalerate and granuloma formation. I., Toxicol. Appl. Pharmacol. 1986, 83, 148 156; Y. Okuno, T. Seki, S. Ito, H. Kaneko, T. Watanabe, T. Yamada, J. Miyamoto, Differential metabolism of fenvalerate and granuloma formation. II., Toxicol. Appl. Pharmacol. 1986, 83, 157 169. [237] J. N. Haselden, D. H. Hutson, P. F. Dodds, The metabolism of 3-phenoxybenzoic acid-containing xenobiotic triacylglycerols in vitro by pancreatic, hormone-sensitive and lipoprotein lipases, Biochem. Pharmacol. 1998, 56, 1591 1598; J. N. Haselden, P. F. Dodds, D. H. Hutson, The metabolism of the xenobiotic triacylglycerols, rac-1- and sn-2-(3-phenoxybenzoyl)-dipalmitoylglycerol, following intravenous administration to the rat, Biochem. Pharmacol. 1998, 56, 1599 1606. [238] U.-W. Wiegand, B. K. Jensen, Pharmacokinetics of acitretin in humans, in Retinoids: 10 Years On, Ed. J.-H. Saurat, Karger, Basel, 1991, p. 192 203; J. J. DiGiovanna, L. A. Zech, M. E. Ruddel, G. Gantt, G. L. Peck, Etretinate: persistent serum levels after long-term therapy, Arch. Dermatol. 1989, 125, 246 251. [239] K. M. Knights, R. Gasser, W, Klemisch, In vitro metabolism of acitretin by human liver microsomes: evidence of an acitretinoyl-coenzyme A thioester conjugate in the transesterification to etretinate, Biochem. Pharmacol. 2000, 60, 507 516; R. C. Chou, R. Wyss, C. A. Huselton, U.-W. Wiegand, A potentially new metabolic pathway: ethyl esterification of acitretin, Xenobiotica 1992, 22, 993 1002; M. A. Polokoff, R. M. Bell, Limited palmitoyl-CoA penetration into microsomal vesicles as evidenced by a highly latent ethanol acyltransferase activity, J. Biol. Chem. 1978, 253, 7173 7178. [240] http://lpi.oregonstate.edu/infocenter/othernuts/carnitine/; A. C. Knapp, L. Todesco, K. Beier, L. Terracciano, H. Sgesser, J. Reichen, S. Krhenbhl, Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores, J. Pharmacol. Exp. Ther. 2008, 324, 568 575. [241] H. Muro, T. Tatsuhara, T. Sugimoto, M. Woo, N. Nishida, K. Murakami, Y. Yamaguchi, Determination of urinary valproylcarnitine by GC-MS with selected-ion monitoring, J. Chromatogr., B 1995, 663, 83 89. [242] B. Melegh, B. Sumegi, A. D. Sherry, Preferential elimination of pivalate with supplemented carnitine via formation of pivaloylcarnitine in man, Xenobiotica 1993, 23, 1255 1261; Q. N. Diep, T. Bhmer, S. Skrede, Formation of pivaloylcarnitine in heart and brown adipose tissue in the rat, Biochim. Biophys. Acta 1995, 1243, 65 70. [243] G. B. Quistad, L. E. Staiger, D. A. Schooley, The role of carnitine in the conjugation of acidic xenobiotics, Drug Metab. Dispos. 1986, 14, 521 525. [244] G. P. Mannaert, P. P. Van Veldhoven, M. Casteels, Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals, Cell Biochem. Biophys. 2000, 32, 73 87; P. P. Van Veldhoven, G. P. Mannaerts, Role and organization of peroxisomal b-oxidation, Adv. Exp. Med. Biol. 1999, 466, 261 272. [245] T. Suga, Drug metabolism in peroxisomes: involvement of peroxisomal b-oxidation system in the oxidative chain-shortening of xenobiotic acyl compounds, Drug Metab. Pharmacokinet. 2003, 18, 155 162. [246] Y. Yamaguchi, R. Norikura, M. Nakanishi, A. Touchi, T. Yoshimori, T. Murakami, T. Baba, K. Mizojiri, T. Matsubara, Sex differences in the metabolism of ()-S-145, a novel thromboxane A2 receptor antagonist in rats, Xenobiotica 1995, 26, 613 626; Y. Yamaguchi, T. Baba, A. Touchi, T. Matsubara, In vitro studies to elucidate the metabolic pathway of ()-S-145, a thromboxane A2 receptor antagonist, in rats, Drug Metab. Dispos. 1995, 23, 1195 1201.
2327
[247] T. Uehara. T. Uemura, S. Hirabayashi, S. Adachi, K. Odaka, H. Akizawa, Y. Magata, T. Irie, Y. Arano, Technetium-99m-labelled long chain fatty acid analogues metabolized by b-oxidation in the heart, J. Med. Chem. 2007, 50, 543 549. [248] M. W. Sinz, A. E. Black, S. M. Bjorge, A. Holmas, B. K. Trivedi, T. F. Woolf, In vitro and in vivo disposition of 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976), Drug Metab. Dispos. 1997, 25, 123 130. [249] C. Li, R. Subramanian, S. Yu, T. Prueksaritanont, Acyl-coenzyme A formation of simastatin in mouse liver preparations, Drug Metab. Dispos. 2006, 34, 102 110; R. A. Halpin, E. H. Ulm, A. E. Till, P. H. Kari, K. P. Vyas, D. B. Hunninghake, D. E. Duggan, Biotransformation of lovastin, Drug Metab. Dispos. 1993, 21, 1003 1011; D. W. Everett, T. J. Chando, G. C. Didonato, S. M. Singhvi, H. Y. Pan, S. H. Weinstein, Biotransformation of pravastatin sodium in humans, Drug Metab. Dispos. 1991, 19, 740 748. [250] M. V. Marsh, J. Caldwell, A. J. Hutt, R. L. Smith, M. W. Horner, E. Houghton, M. S. Moss, 3Hydroxy- and 3-keto-3-phenylpropionic acids: novel metabolites of benzoic acid in horse urine, Biochem. Pharmacol. 1982, 31, 3225 3230; M. V. Marsh, J. Caldwell, R. L. Smith, M. W. Horner, E. Houghton, M. S. Moss, Metabolic conjugation of some carboxylic acids in the horse, Xenobiotica 1981, 11, 655 663. [251] H. Miyazaki, H. Takayama, Y. Minatogawa, K. Miyano, A novel metabolic pathway in the metabolism of 5-(4-chloro-n-butyl)picolinic acid, Biomed. Mass Spectrom. 1976, 3, 140 145; M. Mizugaki, M. Sagi, H. Yamanaka, H. Takayama, M. Ishibashi, H. Miyazaki, Chain elongation of fusaric acid and related compounds in rat liver, J. Biochem. 1986, 99, 469 476. [252] I. Tegeder, K. Williams, G. Geisslinger, Metabolic chiral inversion of 2-arylpropionic acids, in Stereochemical Aspects of Drug Action and Disposition, Eds. M. Eichelbaum, B. Testa, A. Somogyi, Springer Verlag, Berlin, 2003, p. 341 354; J. M. Mayer, M. Roy-de Vos, C. Audergon, B. Testa, Interactions between the in vitro metabolism of xenobiotics and fatty acids. The case of ibuprofen and other chiral profens, Arch. Toxicol. Suppl. 1995, 17, 499 513. [253] H. Hao, G. Wang, J. Sun, Enantioselective pharmacokinetics of ibuprofen and involved mechanisms, Drug Metab. Rev. 2005, 37, 215 234; A. M. Evans, Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs, Eur. J. Clin. Pharmacol. 1992, 42, 237 256; J. M. Mayer, B. Testa, Pharmacodynamics, pharmacokinetics and toxicity of ibuprofen enantiomers, Drugs Future 1997, 22, 1347 1366. [254] R. Brugger, C. Reichel, B. Garcia Alia, K. Brune, T. Yamamoto, I. Tegeder, G. Geisslinger, Expression of rat liver long-chain acyl-CoA synthetase and characterization of its role in the metabolism of R-ibuprofen and other fatty acid-like xenobiotics, Biochem. Pharmacol. 2001, 61, 651 656; A. Soraci, E. Benoit, In vitro fenoprofenyl-coenzyme A thioester formation: interspecies variation, Chirality 1995, 7, 534 540; St. D. Hall, Q. Xiaotao, The role of coenzyme A in the biotransformation of 2-arylpropionic acids, Chem.-Biol. Interact. 1994, 90, 235 251. [255] B. Testa, J. M. Mayer, Chiral recognition in biochemical pharmacology: An overview, in Stereochemical Aspects of Drug Action and Disposition, Eds. M. Eichelbaum, B. Testa, A. Somogyi, Springer Verlag, Berlin, 2003, p. 143 159. [256] W. Schmitz, H. M. Helander, J. K. Hiltunen, E. Conzelmann, Molecular cloning of cDNA species for rat and mouse liver a-methylacyl-CoA racemases, Biochem. J. 1997, 326, 883 889; S. Ferdinandusse, S. Denis, L. IJlst, G. Dacremont, H. R. Waterham, R. J. Wanders, Subcellular localization and physiological role of alpha-methylacyl-CoA racemase, J. Lipid Res. 2000, 41, 1890 1896; M. D. Lloyd, D. J. Darley, A. S. Wierzbicki, M. D. Threadgill, Alpha-methylacyl-CoA racemase an obscure metabolic enzyme takes centre stage, FEBS J. 2008, 275, 1089 1102. [257] D. A. Cuebas, C. Phillips, W. Schmitz, E. Conzelmann, D. K. Novikov, The role of alphamethylacyl-CoA racemase in bile acid synthesis, Biochem. J. 2002, 363, 801 807; S. Ikegawa, T. Goto, H. Owatanabe, J. Goto, Stereoisomeric bio-inversion of (25R)- and (25S)-3a,7a,12atrihydroxy-5b-cholestanoic acid CoA thioesters in rat liver peroxisome, Enantiomer 1997, 2, 333 342; K. Savolainen, T. J. Kotti, W. Schmitz, T. I. Savolainen, R. T. Sormunen, M. Ilves, S. J. Vainio, E. Conzelmann, J. K. Hiltunen, A mouse model for alpha-methylacyl-CoA racemase deficiency:
2328
[258]
[259]
[260] [261]
[262]
[263]
[264]
[265]
[266]
[267]
[268]
adjustement of bile acid synthesis and intolerance to dietary methyl-branched lipids, Hum. Mol. Genet. 2004, 13, 955 965. G. Ding, Y. Liu, J. Sun, Y. takeuchi, T. Toda, T. Hayakawa, S. Fukushima, S. Kishimoto, W. Lin, N. Inotsume, Effect of absorption rate on pharmacokinetics of ibuprofen in relation to chiral inversion in humans, J. Pharm. Pharmacol. 2007, 59, 1509 1513; S. C. Tan, B. K. Patel, S. H. Jackson, C. G. Swift, A. J. Hutt, Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers, Br. J. Clin. Pharmacol. 2003, 55, 579 587; S. C. Tan, B. K. Patel, S. H. Jackson, C. G. Swift, A. J. Hutt, Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers, Xenobiotica 2002, 32, 683 697; H. Cheng, J. D. Rogers, J. L. Demetriades, S. D. Holland, J. R. Seibold, E. Depuy, Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans, Pharm. Res. 1994, 11, 824 830. D. Kantoci, W. J. Wechter, Calculation of inversion half-lives of arylpropionic acid class nonsteroidal antiinflammatory drugs, J. Clin. Pharmacol. 1996, 36, 500 504; N. G. Grubb, D. W. Rudy, D. C. Brater, S. D. Hall, Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a futile cycle of elimination, Br. J. Clin. Pharmacol. 1999, 48, 494 500; A. Rubin, M. P. Knadler, P. P. Ho, L. D. Bechtol, R. L. Wolen, Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans, J. Pharm. Sci. 1985, 74, 82 84; R. G. Simmonds, T. J. Woodage, S. M. Duff, J. N. Green, Stereospecific inversion of (R)()-benoxaprofen in rat and man, Eur. J. Drug Metab. Pharmacokinet. 1980, 5, 169 172. G. Aberg, V. B. Ciofalo, R. G. Pendleton, G. Ray, D. Weddle, Inversion of (R)- to (S)-ketoprofen in eight animal species, Chirality 1995, 7, 383 387. H. Yoshida, Y. Kohno, H. Endo, J. Yamaguchi, K. Fukushima, T. Suwa, M. Hayashi, Mechanistic studies on metabolic chiral inversion of 4-(4-methylphenyl)-2-methylthiomethyl-4-oxobutanoic acid (KE-748), an active metabolite of the new anti-rheumatic agent 2-acetylthiomethyl-4-(4methylphenyl)-4-oxobutanoic acid (KE-298), in rat, Biochem. Pharmacol. 1997, 53, 179 187. S. Ferdinandusse, H. Rusch, A. E. van Lint, G. Dacremont, R. J. Wanders, P. Vreken, Stereochemistry of the peroxisomal branched-chain fatty acid alpha- and beta-oxidation systems in patients suffering from different peroxisomal disorders, J. Lipid Res. 2002, 43, 438 444. A. Meister, Glutathione metabolism and its selective modification, J. Biol. Chem. 1988, 283, 17205 17208; L. D. DeLeve, N. Kaplowitz, Glutathione metabolism and its role in hepatotoxicity, Pharmacol. Ther. 1991, 52, 287 307; H. Sies, Glutathione and its role in cellular functions, Free Radical Biol. Med. 1999, 27, 916 921. D. Burg, G. J. Mulder, Glutathione conjugates and their synthetic derivatives as inhibitors of glutathione-dependent enzymes involved in cancer and drug resistance, Drug Metab. Rev. 2002, 34, 821 863; S. Bharath, M. Hsu, D. Kaur, S. Rajagopalan, J. K. Andersen, Glutathione, iron and Parkinsons disease, Biochem. Pharmacol. 2002, 64, 1037 1048. P. S. Samiec, C. Drews-Botsch, E. W. Flagg, J. C. Kurtz, P. Sternberg Jr., R. L. Reed, D. P. Jones, Glutathione in human plasma: decline in associaiton with aging, age-related macular degeneration, and diabetes, Free Radical Biol. Med. 1998, 24, 699 704; A. Pompella, A. Visvikis, A. Paolicchi, V. De Tata, A. F. Casini, The changing faces of glutathione, a cellular protagonist, Biochem. Pharmacol. 2003, 66, 1499 1503; G. A. Morales, E. Laborde, Small-molecule inhibitors of glutathione S-transferase P1-1 as anticancer therapeutic agents, Annu. Rep. Med. Chem. 2007, 42, 321 335. E. Madej, P. Wardman, The oxidizing power of the glutathione thiyl radical as measured by its electrode potential at physiological pH, Arch. Biochem. Biophys. 2007, 462, 94 102; K. K. Millis, K. H. Weaver, D. L. Rabenstein, Oxidation/reduction potential of glutathione, J. Org. Chem. 1993, 58, 4144 4146. D. A. Dickinson, H. J. Forman, Cellular glutathione and thiols metabolism, Biochem. Pharmacol. 2002, 64, 1019 1026; R. P. Mason, D. N. R. Rao, Thiyl free radical metabolites of thiol drugs, glutathione, and proteins, Methods Enzymol. 1990, 186, 318 329. J. E. Biaglow, M. E. Varnes, E. R. Epp, E. P. Clark, S. W. Tuttle, K. D. Held, Role of glutathione and other thiols in cellular reponse to radiation and drugs, Drug Metab. Rev. 1989, 20, 1 12; D. Ross,
2329
[269]
[270]
[271]
[272]
[273]
[274]
[275]
[276]
[277]
[278]
Glutathione, free radicals and chemotherapeutic agents Mechanisms of free-radical induced toxicity and glutathione-dependent protection, Pharmacol. Ther. 1988, 37, 231 249. C. C. Winterbourn, D. Metodiewa, The reaction of superoxide with reduced glutathione, Arch. Biochem. Biophys. 1994, 314, 284 290; A. Meister, On the antioxidant effects of ascorbic acid and glutathione, Biochem. Pharmacol. 1992, 44, 1905 1915; R. I. M. van Haaften, G. R. M. M. Haenen, C. T. A. Evelo, A. Bast, Effect of vitamin E on glutathione-dependent enzymes, Drug Metab. Rev. 2003, 35, 215 253. H. H. Mansour, H. F. Hafez, N. M. Fahmy, N. Hanafi, Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats, Biochem. Pharmacol. 2008, 75, 773 780; J. Navarro, E. Obrador, J. A. Pelliger, M. Asensi, J. Vina, J. M. Estrella, Blood glutathione as an index of radiation-induced oxidative stress in mice and humans, Free Radical Biol. Med. 1997, 22, 1203 1209; J. B. Mitchell, J. E. Biaglow, A. Russo, Role of glutathione and other endogenous thiols in radiation protection, Pharmacol. Ther. 1988, 39, 269 274. J. D. Hayes, J. U. Flanagan, I. R. Jowsey, Glutathione transferases, Annu. Rev. Pharmacol. Toxicol. 2005, 45, 51 88; D. Sheenan, G. Meade, V. M. Foley, C. A. Dowd, Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily, Biochem. J. 2001, 360, 1 16. J. D. Hayes, D. J. Pulford, The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance, Crit. Rev. Biochem. Mol. Biol. 1995, 30, 445 600; S. Tsuchida, K. Sato, Glutathione transferases and cancer, Crit. Rev. Biochem. Mol. Biol. 1992, 27, 337 384. P. G. Board, G. Chelvanayagam, L. S. Jermin, N. Tetlow, H.-F. Tzeng, M. W. Anders, A. C. Blackburn, Identification of novel glutathione transferases and polymorphic variants by expressed sequence tag database analysis, Drug Metab. Dispos. 2001, 29, 544 547; A. Robinson, G. A. Huttley, H. S. Booth, P. G. Board, Modelling and bioinformatics studies of the human kappa-class glutathione transferase predict a novel third glutathione transferase family with similarity to prokaryotic 2-hydroxy-2-carboxylate isomerases, Biochem. J. 2004, 379, 541 552; I. R. Jowsey, R. E. Thomson, T. C. Orton, C. R. Elcombe, J. D. Hayes, Biochemical and genetic characterization of a murine class kappa glutathione S-transferase, Biochem. J. 2003, 373, 559 569. B. Mukherjee, O. E. Salavaggione, L. L. Pelleymounter, I. Moon, B. W. Eckloff, D. J. Schaid, E. D. Wieben, R. M. Weinshilboum, Glutathione S-transferase omega 1 and omega 2 pharmacogenetics, Drug Metab. Dispos. 2006, 34, 1237 1246; M. Schnekenburger, F. Morceau, A. Duvoix, S. Delhalle, C. Trentesaux, M. Dicato, M. Diederich, Increased glutathione S-transferase P1-1 expression by mRNA stabilization in hemin-indiced differentiation of K562 cells, Biochem. Pharmacol. 2004, 68, 1269 1277; I. R. Jowsey, A. M. Thomson, J. U. Flanagan, P. R. Murdock, G. B. T. Moore, D. J. Meyer, G. J. Murphy, S. A. Smith, J. D. Hayes, Mammalian class sigma glutathione S-transferases: catalytic properties and tissue specific expression of human and rat GSH-dependent prostaglandin D2 synthases, Biochem. J. 2001, 359, 507 516. a) R. N. Armstrong, Structure, catalytic mechanism, and evolution of the glutathione transferases, Chem. Res. Toxicol. 1997, 10, 2 18; b) E. M. van der Aar, K. T. Tan, J. N. M. Commandeur, N. P. E. Vermeulen, Strategies to characterize the mechanisms of action of glutathione S-transferases: a review, Drug Metab. Rev. 1998, 30, 569 643. A. Parraga, I. Garcia-Saez, S. B. Walsh, T. J. Mantle, M. Coll, The three-dimensional structure of a class-Pi glutathione S-transferase complexed with glutathione: the active-site hydration provides insights into the reaction mechanism, Biochem. J. 1998, 333, 811 816. K.-H. Kong, K. Takasu, H. Inoue, K. Takahashi, Tyrosine-7 in human class Pi glutathione Stransferase is important for lowering the pKa of the thiol group of glutathione in the enzymeglutathione complex, Biochem. Biophys. Res. Commun. 1992, 184, 194 197; S. Liu, P. Zhang, X. Ji, W. W. Johnson, G. L. Gilliland, R. N. Armstrong, Contribution of tyrosine 6 to the catalytic mechanism of isoenzyme 3-3 of glutathione S-transferase, J. Biol. Chem. 1992, 267, 4296 4299. K. Satoh, R. Sato, T. Takahata, S. Suzuki, M. Hayakari, S. Tsuchida, I. Hatayama, Quantitative differences in the active-site hydrophobicity of five human glutathione S-transferases, Arch. Biochem. Biophys. 1999, 361, 271 276.
2330
[279] A. M. Caccuri, P. Ascenzi, G. Antonini, M. W. Parker, A. J. Oakley, E. Chiessi, M. Nuccetelli, A. Battistoni, A. Bellizia, G. Ricci, Structural flexibility modulates the activity of human glutathione transferase P1-1, J. Biol. Chem. 1996, 271, 16193 16198. [280] a) B. Ketterer, The role of nonenzymatic reactions of glutathione in xenobiotic metabolism, Drug Metab. Rev. 1982, 13, 161 187; b) B. Testa, Nonenzymatic contributions to xenobiotic metabolism, Drug Metab. Rev. 1982, 13, 25 50. [281] a) B. Coles, Effects of modifying structure on electrophilic reactions with biological nucleophiles, Drug Metab. Rev. 1984, 15, 1307 1334; b) B. Ketterer, Detoxication reactions of glutathione and glutathione transferases, Xenobiotica 1986, 16, 957 973. [282] J. Seidegard, G. Ekstrm, The role of human glutathione transferases and epoxide hydrolases in the metabolism of xenobiotics, Environ. Health Perspect. 1997, 105, 791 799. [283] a) N. Masubuchi, C. Makino, N. Murayama, Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediates: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans, Chem. Res. Toxicol. 2007, 20, 455 464; b) R. Rinaldi, E. Eliasson, S. Swedmark, R. Morgenstern, Reactive intermediates and the dynamics of glutathione transferases, Drug Metab. Dispos. 2002, 30, 1053 1058; c) B. Ketterer, G. J. Mulder, Glutathione conjugation, in Conjugation Reactions in Drug Metabolism, Ed. G. J. Mulder, Taylor & Francis, London, 1990, p. 307 364. [284] E. M. J. Gillam, The dark side of a detoxification mechanism, Trends Pharmacol. Sci. 2001, 22, 11; W. Dekant, S. Vamvakas, Glutathione-dependent bioactivation of xenobiotics, Xenobiotica 1993, 23, 873 887; M. W. Anders, W. Dekant, S. Vamvakas, Glutathione-dependent toxicity, Xenobiotica 1992, 22, 1135 1145. [285] J. N. M. Commandeur, G. J. Stijntjes, N. P. E. Vermeulen, Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates, Pharmacol. Rev. 1995, 47, 271 330. [286] Y. Toyoda, Y. Hagiya, T. Adachi, K. Hoshijima, M. T. Kuo, T. Ishikawa, MRP class of human ATP binding cassette (ABC) transporters: historical background and new research directions, Xenobiotica 2008, 38, 833 862; D. Keppler, Export pumps for glutathione S-conjugates, Free Radical Biol. Med. 1999, 27, 985 991. [287] P. R. Kearns, A. G. Hall, Glutathione and the response of malignant cells to chemotherapy, Drug Discovery Today 1998, 3, 113 121. [288] C. A. Hinchman, H. Matsumoto, T. W. Simmons, N. Ballatori, Intrahepatic conversion of a glutathione conjugate to its mercapturic acid, J. Biol. Chem. 1991, 266, 22179 22185. [289] C. Jsch, H. Sies, T. P. M. Akerboom, Hepatic mercapturic acid formation: involvement of cytosolic cysteinylglycine S-conjugate dipeptidase activity, Biochem. Pharmacol. 1998, 56, 763 771. [290] D. Newman, N. Abuladze, K. Scholz, W. Dekant, V. Tsuprun, S. Ryazantsev, G. Bondar, P. Sassani, I. Kurtz, A. Pushkin, Specificity of aminoacylase III-mediated deacetylation of mercapturic acids, Drug Metab. Dispos. 2007, 35, 43 50. [291] S. B. Park, J. D. Osterloh, S. Vamvakas, M. Hashmi, M. W. Anders, J. R. Cashman, Flavincontaining monooxygenase-dependent stereoselective S-oxygenation and cytotoxicity of cysteine-Sconjugates and mercapturates, Chem. Res. Toxicol. 1992, 5, 193 201. [292] M. P. Gramcsik, K. K. Millis, T. G. Hamill, Kinetics of the conjugation of aniline mustards with glutathione and thiosulfate, Chem.-Biol. Interact. 1997, 105, 35 52; H. A. A. M. Dirven; B. van Ommen, P. J. van Bladeren, Glutathione conjugation of alkylating cytostatic drugs with a nitrogen mustard group and the role of glutathione S-transferases, Chem Res. Toxicol. 1996, 9, 351 360. [293] M. P. Gramcsik, T. G. Hamill, M. Colvin, NMR studies of the conjugation of mechlorethamine with glutathione, J. Med. Chem. 1990, 33, 1009 1014. [294] A. P. Henderson, M. L. Barnes, C. Bleasdale, R. Cameron, W. Clegg, S. L. Heath, A. B. Lindstrom, S. M. Rappaport, S. Waidyanatha, W. P. Watson, B. T. Golding, Reactions of benzene oxide with thiols including glutathione, Chem. Res. Toxicol. 2005, 18, 265 270. [295] P. Upadhyaya, P. Rao, J. B. Hochalter, Z. Li, P. W. Villalta, S. S. Hecht, Quantification of N-acetylS-(9,10-dihydro-9-hydroxy-10-phenanthryl)-d-cysteine in human urine: comparison with glutathione-S-transferase genotypes in smokers, Chem. Res. Toxicol. 2006, 19, 1234 1240.
2331
[296] R. A. Kemper, R. J. Krause, A. A. Elfarra, Metabolism of butadiene monoxide by freshly isolated hepatocytes from mice and rats: different partitioning between oxidative, hydrolytic, and conjugation pathways, Drug Metab. Dispos. 2001, 29, 830 836. [297] J. E. Sharer, R. J. Duescher, A. A. Elfarra, Formation, stability, and rearrangements of the glutathione conjugates of butadiene monoxide: evidence for the formation of stable sulfurane intermediates, Chem. Res. Toxicol. 1991, 4, 430 436. [298] I. Linhart, Stereochemistry of styrene biotransformation, Drug Metab. Rev. 2001, 33, 353 367; P. Vodicka, M. Koskinen, A. Naccarati, B. Oesch-Bartlomowicz, L. Vodickova, K. Hemminki, F. Oesch, Styrene metabolism, genotoxicity, and potential carcinogenicity, Drug Metab. Rev. 2006, 38, 805 853. [299] J. Y. Zjang, J. J. Yuan, Y. F. Wang, R. H. Bible Jr., A. P. Breau, Pharmacokinetics and metabolism of a COX-2 inhibitor, valdecoxib, in mice, Drug Metab. Dispos. 2003, 31, 491 501. [300] R. Subramanian, X. Fang, T. Prueksaritanont, Structural characterizaiton of in vivo rat glutathione adducts and a hydroxylated metabolite of simvastatin hydroxy acid, Drug Metab. Dispos. 2002, 30, 225 230. [301] J. Chen, R. N. Armstrong, Stereoselective catalysis of a retro-Michael reaction by class mu glutathione transferases. Consequences for the internal distribution of products in the active site, Chem. Res. Toxicol. 1995, 8, 580 585. [302] T. A. Baillie, K. Kassahun, Reversibility in glutathione-conjugate formation, Adv. Pharmacol. 1994, 27, 163 181. [303] a) K. Berhane, M. Widersten, . Engstrm, J. W. Kozarich, B. Mannervik, Detoxication of base propenals and other a,b-unsaturated aldehyde products of radical reactions and lipid peroxidation by human glutathione transferases, Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 1480 1484; b) P. S. Portoghese, G. S. Kedziora, D. L. Larson, B. K. Bernard, R. L. Hall, Reactivity of glutathione with a,b-unsaturated ketone flavouring substances, Food Chem. Toxicol. 1989, 27, 773 776; c) E. Boyland, L. F. Chasseaud, Enzyme-catalysed conjugations of glutathione with unsaturated compounds, Biochem. J. 1967, 104, 95 102. [304] S. C. J. Sumner, L. Selvaraj, S. K. Nauhaus, T. R. Fennell, Urinary metabolites from F344 rats and B6C3F1 mice coadministered acrylamide and acrylonitrile for 1 or 5 days, Chem. Res. Toxicol. 1997, 10, 1152 1160. [305] T. Ishida, Y. Kumagai, Y. Ikeda, K. Ito, M. Yano, S. Toki, K. Mihashi, T. Fujioka, Y. Iwase, S. Hachiyama, (8S)-(Glutathion-S-yl)dihydromorphinone, a novel metabolite of morphine from guinea pig bile, Drug Metab. Dispos. 1989, 17, 77 81. [306] S. Awasthi, S. K. Srivastava, F. Ahmad, H. Ahmad, G. A. S. Ansari, Interactions of glutathione Stransferase-p with ethacrynic acid and its glutathione conjugate, Biochim. Biophys. Acta 1993, 1164, 173 178. [307] D. A. Nicholl-Griffith, N. Gupta, S. P. Twa, H. Williams, L. A. Trimble, J. A. Yergey, Verlukast (MK-0679) conjugation with glutathione by rat liver and kidney cytosols and excretion in the bile, Drug Metab. Dispos. 1995, 23, 1085 1093. [308] B. I. Eklund, S. Gunnarsdottir, A. E. Elfarra, B. Mannervik, Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs, Biochem. Pharmacol. 2007, 73, 1829 1841. [309] H. Nohl, W. Jordan, R. J. Youngman, Quinones in biology: functions in electron transfer and oxygen activation, Adv. Free Radical Biol. Med. 1986, 2, 211 279. [310] M. Y. Moridani, H. Scobie, A. Jamshidzadeh, P. Salehi, P. J. OBrien, Caffeic acid, chlorogenic acid, and dihydrocaffeic acid metabolism: glutathione conjugate formation, Drug Metab. Dispos. 2001, 29, 1432 1439. [311] F. Bai, S. S. Lau, T. J. Monks, Glutathione and N-acetylcysteine conjugates of a-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity, Chem. Res. Toxicol. 1999, 12, 1150 1157. [312] M. M. C. G. Peters, S. S. Lau, D. Dulik, D. Murphy, B. van Ommen, P. J. van Bladeren, T. J. Monks, Metabolism of tert-butylhydroquinone to S-substituted conjugates in the male Fischer 344 rat, Chem. Res. Toxicol. 1996, 9, 133 139.
2332
[313] T. J. Monks, S. S. Lau, Biological reactivity of polyphenolic-glutathione conjugates, Chem. Res. Toxicol. 1997, 10, 1296 1313; T. J. Monks, S. S. Lau, The pharmacology and toxicology of polyphenolic-glutathione conjugates, Annu. Rev. Pharmacol. Toxicol. 1998, 38, 229 255. [314] K. S. Smith, P. L. Smith, T. N. Heady, J. M. Trugman, W. D. Harman, T. L. Macdonald, In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity, Chem. Res. Toxicol. 2003, 16, 123 128. [315] D. Dalvie, E. Smith, A. Deese, S. Bowlin, In vitro metabolic activation of thiabendazole via 5hydroxythiabendazole: identification of a glutathione conjugate of 5-hydroxythiabendazole, Drug Metab. Dispos. 2006, 34, 709 717. [316] J. L. Bolton, J. C. Y. Le Blanc, K. W. M. Siu, Reactions of quinone methides with proteins: analysis of myoglobin adduct formation by electrospray mass spectrometry, Biol. Mass Spectrom. 1993, 22, 666 668; D. C. Thompson, J. A. Thompson, M. Sugumaran, P. Moldeus, Biological and toxicological consequences of quinone methide formation, Chem.-Biol. Interact. 1992, 86, 129 162. [317] D. Thompson, D. Constantin-Teodosiu, B. Egestad, H. Mickos, P. Moldeus, Formation of glutathione conjugates during oxidation of eugenol by microsomal fractions of rat liver and lung, Biochem. Pharmacol. 1990, 39, 1587 1595. [318] H. M. Awad, M. G. Boersma, S. Boeren, P. J. van Bladeren, J. Vervoort, I. M. C. M. Rietjens, The regioselectivity of glutathione adduct formation with flavonoid quinone/quinone methides is pHdependent, Chem. Res. Toxicol. 2002, 15, 343 351; M. G. Boersma, J. Vervoort, H. Szymusiak, K. Lemanska, B. Tyrakowska, N. Cenas, J. Segura-Aguilar, I. M. C. M. Rietjens, Regioselectivity and reversibility of the glutathione conjugation of quercetin quinone methide, Chem. Res. Toxicol. 2000, 13, 185 191. [319] N. Novak, J. Lin, Reactions of glutathione with carcinogenic esters of N-arylhydroxamic acids, J. Am. Chem. Soc. 1996, 118, 1302 1308. [320] M. W. Anders, Glutathione-dependent bioactivation of haloalkanes and haloalkenes, Drug Metab. Rev. 2004, 36, 583 594; M. W. Anders, W. Dekant, Glutathione-dependent bioactivation of haloalkenes, Annu. Rev. Pharmacol. Toxicol. 1998, 38, 501 537. [321] L. J. Jolivette, M. W. Anders, Structure-activity relationship for the biotransformation of haloalkenes by rat liver microsomal glutathione transferase I, Chem. Res. Toxicol. 2002, 15, 1036 1041; S. J. Hargus, M. E. Fitzsimmons, Y. Aniya, M. W. Anders, Stereochemistry of the microsomal glutathione S-transferase catalyzed addition of glutathione to chlorotrifluoroethene, Biochemistry 1991, 30, 717 721. [322] M. B. Finkelstein, R. B. Baggs, M. W. Anders, Nephrotoxicity of the glutathione and cysteine conjugates of 2-bromo-2-chloro-1,1-difluoroethene, J. Pharmacol. Exp. Ther. 1992, 261, 1248 1252; J. N. M. Commandeur, F. J. J. De Kanter, N. P. E. Vermeulen, Bioactivation of the cysteine-Sconjugate and mercapturic acid of tetrafluoroethylene to acylating reactive intermediates in the rat: dependence of activation and deactivation activities on acetyl coenzyme A availability, Mol. Pharmacol. 1989, 36, 654 663. [323] H. Orhan, J. N. M. Commandeur, G. Sahin, U. Aypar, A. Sahin, N. P. E. Vermeulen, Use of 19FNMR and GC-electron capture detection in the quantitative analysis of fluorine-containing metabolites in urine of sevoflurane-anesthetized patients, Xenobiotica 2004, 34, 301 316; T. G. Altuntas, S. B. Park, E. D. Kharasch, Sulfoxidation of cysteine and mercapturic acid conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), Chem. Res. Toxicol. 2004, 17, 435 445; R. A. Iyer, R. B. Baggs, M. W. Anders, Nephrotoxicity of the glutathione and cysteine S-conjugates of the sevoflurane degradation product 2-(fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A) in male Fischer 344 rats, J. Pharmacol. Exp. Ther. 1997, 283, 1544 1551. [324] W. Kanhai, M. Koob, W. Dekant, D. Henschler, Metabolism of 14C-dichloroethyne in rats, Xenobiotica 1991, 21, 905 916. [325] S. L. Iverson, J. P. Uetrecht, Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity, Chem. Res. Toxicol. 2001, 14, 175 181. [326] J. R. Bucher, Methyl isocyanate: a review of health effects research since Bhopal, Fundam. Appl. Toxicol. 1987, 9, 367 379.
2333
[327] J. G. Slatter, M. S. Rashed, P. G. Pearson, D. H. Han, T. A. Baillie, Biotransformation of methyl isocyanate in the rat. Evidence for glutathione conjugation as a major pathway of metabolism and implications for isocyanate-mediated toxicities, Chem. Res. Toxicol. 1991, 4, 157 161. [328] T. A. Baillie, J. G. Slatter, Glutathione: A vehicle for the transport of chemically reactive metabolites in vivo, Acc. Chem. Res. 1991, 24, 264 270. [329] R. W. Lange, B. W. Day, R. Lemus, V. A. Tyurin, V. E. Kagan, M. H. Karol, Intracellular Sglutathionyl adducts in murine lung and human bronchoepithelial cells after exposure to diisocyanatotoluene, Chem. Res. Toxicol. 1999, 12, 931 936. [330] A. G. Borel, F. S. Abbott, Characterization of novel isocyanate-derived metabolites of the formamide N-formylamphetamine with the combined use of electrospray MS and stable isotope methodology, Chem. Res. Toxicol. 1995, 8, 891 899. [331] C. M. Jochheim, M. R. Davis, K. M. Baillie, W. J. Ehlhardt, T. A. Baillie, Glutathione-dependent metabolism of the antitumor agent sulofenur. Evidence for the formation of p-chlorophenyl isocyanate as a reactive intermediate, Chem. Res. Toxicol. 2002, 15, 240 248. [332] K. Kassahun, M. Davis, P. Hu, B. Martin, T. Baillie, Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase I metabolites and glutathione conjugates, Chem. Res. Toxicol. 1997, 10, 1228 1233. [333] D. J. Meyer, D. J. Crease, B. Ketterer, Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates, Biochem. J. 1995, 306, 565 569; R. H. Kolm, U. H. Danielson, Y. Zhang, P. Talalay, B. Mannervik, Isothiocyanates as substrates for human glutathione transferases: structure-activity studies, Biochem. J. 1995, 311, 453 459. [334] F. P. Guengerich, W. A. McCormick, J. B. Wheeler, Analysis of the kinetic mechanism of haloalkane conjugation by mammalian theta-class glutathione transferases, Chem. Res. Toxicol. 2003, 16, 1493 1499. [335] C. A. W. Snel, S. Mahadevan, M. Polhuij, G. J. Mulder, Glutathione conjugation and pharmacokinetics of 2-bromo-3-phenylpropionic acid in vitro and in the rat in vivo, Chirality 1992, 4, 407 414. [336] K. Watanabe, F. P. Guengerich, Limited reactivity of formyl chloride with glutathione and relevance to metabolism and toxicity of dichloromethane, Chem. Res. Toxicol. 2006, 19, 1091 1096; G. A. Marsch, S. Botta, M. V. Martin, W. A. McCormick, F. P. Guengerich, Formation and mass spectrometric analysis of DNA and nucleoside adducts by S-(1-acetoxymethyl)glutathione and by glutathione S-transferase-mediated activation of dihalomethanes, Chem. Res. Toxicol. 2004, 17, 45 54; J. B. Wheeler, N. V. Stourman, R. Thier, A. Dommermuth, S. Vuilleumier, J. A. Rose, R. N. Armstrong, F. P. Guengerich, Conjugation of haloalkanes by bacterial and mammalian glutathione transferases: mono- and dihalomethanes, Chem. Res. Toxicol. 2001, 14, 1118 1127; M. K. Ross, R. A. Pegram, Glutathione transferase theta 1-1-dependent metabolism of the water disinfection byproduct bromodichloromethane, Chem. Res. Toxicol. 2003, 16, 216 226. [337] M. Hashmi, S. Dechert, W. Dekant, M. W. Anders, Bioactivation of [13C]dichloromethane in mouse, rat, and human liver cytosol: 13C NMR spectroscopic studies, Chem. Res. Toxicol. 1994, 7, 291 296; E. Hallier, K. R. Schrder, K. Asmuth, A. Dommermuth, B. Aust, H. W. Goergens, Metabolism of dichloromethane to formaldehyde in human erythrocytes: influence of polymorphism of glutathione transferase theta (GST T1-1), Arch. Toxicol. 1994, 68, 423 427; G. A. Marsch, R. G. Mundkowski, B. J. Morris, M. L. Manier, M. K. Hartman, F. P. Guengerich, Characterization of nucleoside and DNA adducts formed by S-(1-acetoxymethyl)glutathione and implications for dihalomethane-glutathione conjugates, Chem. Res. Toxicol. 2001, 14, 600 608. [338] S. K. Lee, C. H. Jin, S. H. Hyun, D. W. Lee, G. H. Kim, T. W. Jeon, J. Lee, D. H. Kim, H. G. Jeong, E. S. Lee, T. C. Jeong, Identification of glutathione conjugates and mercapturic acids of 1,2dibromopropane in female BALB/c mice by liquid chromatography-electrospray ionization tandem MS, Xenobiotica 2005, 35, 97 105; J. B. Wheeler, N. V. Stourman, R. N. Armstrong, F. P. Guengerich, Conjugation of haloalkanes by bacterial and mammalian glutathione transferases: mono- and vicinal dihaloethanes, Chem. Res. Toxicol. 2001, 14, 1107 1117; T. Shimada, H. Yamazaki, Y. Oda, A. Hiratsuka, T. Watabe, F. P. Guengerich, Activation and inactivation of
2334
[339]
[340] [341] [342]
[343]
[344]
[345]
[346]
[347] [348] [349]
[350]
carcinogenic dihaloalkanes and other compounds by glutathione S-transferase 5-5 in Salmonella typhimurium tester strain NM5004, Chem. Res. Toxicol. 1996, 9, 333 340; N. A. Mahmood, D. Overstreet, L. T. Burka, Comparative disposition and metabolism of 1,2,3-trichloropropane in rats and mice, Drug Metab. Dispos. 1991, 19, 411 418. E. J. Sderlund, D. J. Meyer, B. Ketterer, S. D. Nelson, E. Dybing, J. A. Holme, Metabolism of 1,2dibromo-3-chloropropane by glutathione S-transferases, Chem.-Biol. Interact. 1995, 97, 257 272; S. A. Kouzi, E. J. Sderlund, E. Dybing, J. H. N. Meerman, S. D. Nelson, Comparative toxicity of ()-(R)- and ()-(S)-1,2-dibromo-3-chloropropane, Chirality 1995, 7, 359 364; P. G. Pearson, E. J. Sderlund, E. Dybing, S. D. Nelson, Metabolic activation of 1,2-dibromo-3-chloropropane: evidence for the formation of reactive episulfonium ion intermediates, Biochemistry 1990, 29, 4971 4981. L. Jin, T. A. Baillie, Mechanism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats, Chem. Res. Toxicol. 1997, 10, 318 327. D. Zhong, Z. Xie, X. Chen, Metabolism of pantoprazole involving conjugation with glutathione in rats, J. Pharm. Pharmacol. 2005, 57, 341 349. J.-Y. Shim, P. F. Boone, A. M. Richard, Theoretical study of the SNV reaction of trichloroethylene (TCE) and CH3S as a model for glutathione conjugation of TCE, Chem. Res. Toxicol. 1999, 12, 308 316. L. H. Lash, W. Qian, D. A. Putt, S. E. Hueni, A. A. Elfarra, R. J. Krause, J. C. Parker, Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences, J. Pharmacol. Exp. Ther. 2001, 297, 155 164; B. S. Cummings, J. C. Parker, L. H. Lash, Role of cytochrome P450 and glutathione S-transferase a in the metabolism and cytotoxicity of trichloroethylene in rat kidney, Biochem. Pharmacol. 2000, 59, 531 543. G. Birner, A. Rutkowska, W. Dekant, N-Acetyl-S-(1,2,2-trichlorovinyl)-l-cysteine and 2,2,2trichloroethanol: two novel metabolites of tetrachloroethene in humans after occupational exposure, Drug Metab. Dispos. 1996, 24, 41 48; A. R. Goeptar, J. N. M. Commandeur, B. van Ommen, P. J. van Bladeren, N. P. E. Vermeulen, Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity. Relevance of the mercapturic acid pathway, Chem. Res. Toxicol. 1995, 8, 3 21. E. M. van der Aar, M. J. de Groot, T. Bouwman, G. J. Bijloo, J. N. M. Commandeur, N. P. E. Vermeulen, 4-Substituted 1-chloro-2-nitrobenzens: SAR and extension of the substrate model of rat glutathione S-transferase 4-4, Chem. Res. Toxicol. 1997, 10, 439 449; A. E. M. F. Soffers, J. H. T. M. Ploemen, M. J. H. Moonen, T. Wobbes, B. van Ommen, J. Vervoort, P. J. van Bladeren, I. M. C. M. Rietjens, Regioselectivity and QSAR for the conjugation of a series of fluoronitrobenzenes by purified glutathione S-transferase enzymes from rat and man, Chem. Res. Toxicol. 1996, 9, 638 646; J. Shang, S. Xu, Y. Teffera, G. A. Doss, R. A. Stearns, S. Edmonson, M. G. Beconi, Metabolic activation of a pentafluorophenylethylamine derivative: formation of glutathione conjugates in vitro in the rat, Xenobiotica 2005, 35, 697 713. D. M. Dulik, J. K. Huwe, J. E. Bakke, M. S. Connors, C. Fenselau, Conjugation of polychlorinated agrochemical sulfoxides and sulfones by glutathione, Xenobiotica 1992, 22, 325 334; Z. Zao, K. A. Koeplinger, T. Peterson, R. A. Conradi, P. S. Burton, A. Suarato, R. L. Heinrikson, A. G. Tomasselli, Mechanism, structure-activity studies, and potential applications of glutathione Stransferase-catalyzed cleavage of sulfonamides, Drug Metab. Dispos. 1999, 27, 992 998. M. M. He, T. L. Abraham, T. J. Lindsay, S. H. Chay, B. A. Czeskis, L. A. Shipley, Metabolism and disposition of moxonidine in Fischer 344 rats, Drug Metab. Dispos. 2000, 28, 446 459. K. Fujioka, J. E. Casida, Glutathione S-transferase conjugation of organophosphorus pesticides yields S-phospho-, S-aryl-, and S-alkylglutathione derivatives, Chem. Res. Toxicol. 2007, 20, 1211 1217. J. C. L. Erve, M. A. Svensson, H. von Euler-Chelpin, E. Klasson-Wehler, Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils, Chem. Res. Toxicol. 2004, 17, 564 571. T. F. Dowsley, K. Reid, D. Petsikas, J. B. Ulreich, R. L. Fisher, P.-G. Forkert, Cytochrome P450dependent bioactivation of 1,1-dichloroethylene to a reactive epoxide in human lung and liver
2335
[351] [352]
[353]
[354] [355] [356] [357]
[358]
[359] [360] [361] [362]
[363]
[364] [365] [366]
[367]
microsomes, J. Pharmacol. Exp. Ther. 1999, 289, 641 648; P.-G. Forkert, In vivo formation and location of 1,1-dichloroethylene epoxide in murine liver: identification of its glutathione conjugate 2-S-glutathionyl acetate, J. Pharmacol. Exp. Ther. 1999, 290, 1299 1306. M. P. Grillo, L. Z. Benet, Interaction of g-glutamyltransferase with clofibryl-S-acyl-glutathione in vitro and in vivo in rats, Chem. Res. Toxicol. 2001, 14, 1033 1040. C. J. Decker, J. R. Cashman, K. Sugiyama, D. Maltby, M. A. Correia, Formation of glutathionylspironolactone disulfide by rat liver cytochrome P450 or hog liver flavin-containing monooxygenases: a functional probe of two-electron oxidations of the thiosteroid?, Chem. Res. Toxicol. 1991, 4, 669 677. K. Kassahun, P. G. Pearson, W. Tang, I. McIntosh, K. Leung, C. Elsmore, D. Dean, R. Wang, G. Doss, T. A. Baillie, Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission, Chem. Res. Toxicol. 2001, 14, 62 70. K. D. Tew, Redox in redux: emergent roles for glutathione S-transferase P (GSTP) in regulation of cell signaling and S-glutathionylation, Biochem. Pharmacol. 2007, 73, 1257 1269. R. Narazaki, K. Harada, A. Sugii, M. Otagiri, Kinetic analysis of the covalent binding of captopril to human serum albumin, J. Pharm. Sci. 1997, 86, 215 219. N. Ballatori, Glutathione mercaptides as transport forms of metals, Adv. Pharmacol. 1994, 27, 271 298. P. D. Oram, X. Fang, Q. Fernando, P. Letkeman, D. Letkeman, The formation constants of mercury(II)-glutathione complexes, Chem. Res. Toxicol. 1996, 9, 709 712; T. Urano, A. Naganuma, N. Imura, Methylmercury-cysteinylglycine constitutes the main form of methylmercury in rat bile, Res. Commun. Chem. Pathol. Pharmacol. 1988, 60, 197 210. M. Lu, H. Wang, X.-F. Li, L. L. Arnold, S. M. Cohen, X. C. Le, Binding of dimethylarsinous acid to Cys-13a of rat hemoglobin is responsible for the retention of arsenic in rat blood, Chem. Res. Toxicol. 2007, 20, 27 37. N. Scott, K. M. Hatledid, N. E. MacKenzie, D. E. Carter, Reactions of arsenic(III) and arsenic(V) species with glutathione, Chem. Res. Toxicol. 1993, 6, 102 106. Z. Gregus, A. Cyurasics, Role of glutathione in the biliary excretion of the arsenical drugs trimelarsan and melarsoprol, Biochem. Pharmacol. 2000, 59, 1375 1385. M. D. Hall, T. W. Hambley, Platinum(IV) antitumour compounds: their bioinorganic chemistry, Coord. Chem. Rev. 2002, 232, 49 67. D. Hagrman, J. Goodisman, A.-K. Souid, Kinetic studies on the reactions of platinum drugs with glutathione, J. Pharmacol. Exp. Ther. 2004, 308, 658 666; J. C. Dabrowiak, J. Goodisman, A.-K. Souid, Kinetic study on the reaction of cisplatin with thiols, Drug Metab. Dispos. 2002, 30, 1378 1384. D. M. Townsend, J. A. Marto, M. Deng, T. J. MacDonald, M. H. Hanigan, HPLC and MS characterization of the nephrotoxic biotransformation products of cisplatin, Drug Metab. Dispos. 2003, 31, 705 713; T. Ishikawa, F. Ali-Osman, Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells, J. Biol. Chem. 1993, 268, 20116 20125. P. G. Board, M. W. Anders, Glutathione transferase omega 1 catalyzes the reduction of S(phenacyl)glutathiones to acetophenones, Chem. Res. Toxicol. 2007, 20, 149 154. P. J. van Bladeren, B. van Ommen, The inhibition of glutathione S-transferases: mechanisms, toxic consequences and therapeutic benefits, Pharmacol. Ther. 1991, 51, 35 46. E. P. Gallagher, J. L. Gardner, D. S. Barber, Several glutathione S-transferase isozymes that protect against oxidative injury are expressed in human liver mitochondria, Biochem. Pharmacol. 2006, 71, 1619 1628. M. K. Ellis, S. Hill, P. M. D. Foster, Reactions of nitrosonitrobenzenes with biological thiols: identification and reactivity of glutathion-S-yl conjugates, Chem.-Biol. Interact. 1992, 82, 151 163; S. Kazanis, R. A. McClelland, Electrophilic intermediates in the reaction of glutathione and nitrosoarenes, J. Am. Chem. Soc. 1992, 114, 3052 3059; D. Gallemann, A. Greif, P. Eyer, H.-U. Wagner, J. Sonnenbichler, I. Sonnenbichler, W. Schfer, I. Buhrow, Additional pathways of S-
2336
[368]
[369] [370]
[371]
[372]
[373] [374] [375]
[376]
[377]
conjugate formation during interaction of 4-nitrosophenethole with glutathione, Chem. Res. Toxicol. 1998, 11, 1411 1422. A. E. Cribb, M. Miller, J. S. Leeder, J. Hill, S. P. Spielberg, Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione Implications for idiosyncratic toxicity, Drug Metab. Dispos. 1991, 19, 900 906. J. P. ODonnell, The reaction of amines with carbonyls: its significance in the nonenzymatic metabolism of xenobiotics, Drug Metab. Rev. 1982, 13, 123 159. W. A. Clementi, J. L. McNay, T. Talseth, K. D. Haegele, T. M. Ludden, G. E. Musgrave, Endogenous generation of hydralazine from labile hydralazine hydrazones, J. Pharmacol. Exp. Ther. 1982, 222, 159 165. . Almarsson, M. J. Kaufman, J. D. Stong, Y. Wu, S. M. Mayr, M. A. Petrich, J. M. Williams, Meropenem exists in equilibrium with a carbon dioxide adduct in bicarbonate solution, J. Pharm. Sci. 1998, 87, 663 666. M. L. Anthony, E. Holmes, P. C. R. McDonnell, T. J. B. Gray, M. Blackmore, J. K. Nicholson, 1H NMR spectroscopic studies on the reactions of haloalkylamines with bicarbonate ions: formation of N-carbamates and 2-oxazolidones in cell culture media and blood plasma, Chem. Res. Toxicol. 1995, 8, 1046 1053. L. P. C. Delbressine, C. W. Funke, M. van Tilborg, F. M. Kaspersen, On the formation of carbamate glucuronides, Xenobiotica 1990, 20, 133 134. C. Senda, S. Toda, M. Tateishi, K. Kobayashi, T. Igarashi, K. Chiba, Mexiletine carbonyloxy b-dglucuronide: a novel metabolite in human urine, Xenobiotica 2003, 33, 871 884. R. S. Obach, A. E. Reed-Hagen, S. S. Krueger, B. J. Obach, T. N. OConnell, K. S. Zandi, S. Miller, J. W. Coe, Metabolism and disposition of varenicline, a selective a4b2 acetylcholine receptor partial agonist, in vivo and in vitro, Drug Metab. Dispos. 2006, 34, 121 130. H. Hayakawa, Y. Fukushima, H. Kato, H. Fukumoto, T. Kadota, H. Yamamoto, H. Kuroiwa, J. Nishigaki, A. Tsuji, Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters, Drug Metab. Dispos. 2003, 31, 1409 1418. L. M. Tremaine, J. G. Stroh, R. A. Ronfeld, Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline, Drug Metab. Dispos. 1989, 17, 58 63; L. M. Tremaine, W. M. Welch, R. A. Ronfeld, Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog, Drug Metab. Dispos. 1989, 17, 542 550. Received June 20, 2008

The Biochemistry of Drug Metabolism - An Introduction

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Biochemistry of Drug Metabolism - An Introduction

Uploaded by

Copyright:

Available Formats

CHEMISTRY & BIODIVERSITY Vol.

REVIEW The Biochemistry of Drug Metabolism An Introduction

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)

CHEMISTRY & BIODIVERSITY Vol. 5 (2008)