Jessica Yohari Winata

Biomedicine - 14010019

Toxicology Assignment

Question
1. a. Explain 1 example of toxic agent which undergo biotransformation process to be:
- More toxic compound (toxication)
- Less toxic compound (detoxication)
b. Describe the process!
Answers
1. Halothane is used in general anesthetic drug. When it comes to biotransformation
process, this compound can become more toxic or less toxic. More toxic compound
occasionally leading to severe hepatitis. This can be happened due to un-metabolized
form of the eliminated dose drug (around 0-80%) during the 24 hours after
administration to the patients. While less toxic compound is metabolized by the
presence of CYP monooxygenase CYP2E1.

Figure 1. Major biotransformation of halothane

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Biomedicine - 14010019
a. Detoxification (less toxic compound)
- The major pathway involves and oxidative step with adding oxygen
atom and formation of halohydrin. The unstable halohydrin loses
hydrobromic acid to become trifluoroacetyl chloride. After that,
undergo hydrolysis steps and turn into trifluoroacetic acid. This final
metabolite will easily excrete through urine.
- In certain condition, which low level oxygen happen, the drug can be
metabolized through the pulmonary excretion.
First pathway, the halothane compound undergo reductive
pathway to produce free radical named 1-chloro-2,2,2trifluoroethyl radical. This initial radical may also cause a
radial attack of polyunsaturated lipids, which produce 1-chloro2,2,2-trifluoroethane then excreted through exhalation.
The second pathway is by one electron reduction from that free
radicals will result in 1-chloro-2,2,2-triluoroethyl carbenion.
Final metabolism through the abstraction of a fluoride ion that
will produce 1-chloro-2,2-difluoroethylene, which can excreted
through exhalation too.

Figure 2. Biotransformation of halothane to become less toxic

(detoxification)

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Biomedicine - 14010019
b. Toxication (more toxic compound)
In conditions of low level oxygen, a reductive pathway (10%) is strengthen
and produce a free radical named 1-chloro-2,2,2-trifluoroethyl radical that will
lead to other process to produce toxic effect of halothane.
o Through the elimination of an -elimination of chloride ion, which
produces trifluoromethylcarbene. It is suggested that the careine
complex might lead to inactivation of the CYP enzyme when combine
with the FEII in the active site. But this inactivation known to be due
to the formation of an iron--alkyl complex that derived from the 1chloro-2,2,2,-trifluoroethyl radical.

Figure 3. Biotransformation of halothane to become toxic effect

(toxication)

Jessica Yohari Winata

Biomedicine - 14010019
o It is suggested that immune reaction toward modified proteins of liver
become the main reason of the halothane hepatoxicity. In fact, when
trifluoroacetyl chloride formed during the oxidative metabolism by
halothane, these proteins are trifluoroacetylated on their -NH2-lysyl
residue. The product of the reaction can acts as a foreign epitope and
the neoantigen (drug-protein conjugate) is elicits an immune response
towards liver.

Figure 4. Biotransformation of halothane to trifluoroacetyl chloride

and the subsequent binding to protein
A related fluorocarbon named HCFC 1,2,3 that used in the air conditioning system is
metabolized to the same acyl halide and was recently implicated in an epidemic of
liver disease in nine workers of a Belgian factory. All patients had serum antibodies to
trifluoroacetylated proteins.

Jessica Yohari Winata

Biomedicine - 14010019
2. Explain various toxic agent which cause adverse effects to development process!
Explain also about the mechanism! (3 examples)
a. Diphenylhydantoin Maternally Mediated Effects
Diphenylhydantoin (DPH) or phenytoin is an anticonvulsant used to
treat epilepsy. Around 11-17% of abnormal development of fetuses might be
happen during drug consumption in pregnant women. These abnormalities
(fetal hydantoin syndrome) include facial dimorphism (epicanthal folds,
hypertelorism, broad, flat bridge of the nose, upturned tip of nose, and
prominent lips), distal digital hypoplasia, intrauterine growth retardation, and
mental retardation.
DPH is metabolized by cytochrome P450 (CYP) enzyme to reactive
intermediates (arene oxide) that form adducts with DNA or protein within the
embryo. Another research suggests that DPH is metabolized by prostaglandin
synthase to a teratogenic intermediated. This research supports by the
observation that DPH teratogenicity in mice can be mitigated by cotreatment
with aspirin (inhibitor of prostaglandin synthetase). It has been observed that
DPH treatment in rodents decrease the expression of the mRNAs for a number
of important growth factors, such as TGF, NT3 and WNT1. But the
mechanism is still unknown, whether due to gene expression or a degradation
of RNA by reactive mediates of DPH.
b. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) Receptor-Ligand Interaction
(chemical interacts with an endogenous cytoplasmic receptor)
TCDD is one of environmental pollutants, results from chlorinated
products, such as herbicides Agent Orange and wood preservatives. Exposure
of TCDD in uterus can causes increased mortality and growth retardation,
structural and behavioral abnormalities.
TCDD acts via intracellular protein (the AhR), which functions as a
ligand-dependent transcription partnership with a second protein (Arnt). AhR
is an important elements on DNA to alter the gene expression (e.q. lower or
higher the affinity receptors).
c. Mercury Interference with Sulfhydryl Groups
Methylmercury (MeHg) known as environmental toxicant that mostly
affects the CNS, kidney and liver (lesser effect). This compound also can
affect the brain by crossing the blood-brain barrier by an amino acid carrier,
called L (leucine-preferring) amino acid. This MeHg will release to reach the
brain capillary endothelial cells into the brain interstitial space as a gluthione
complex. MeHg maintained a high affinity for thiol group that bind to
endogenous sulfhydryl-containing ligands, such as protein, glutathione that
found in the blood and tissue.
Exposure by this compound can cause changes in neuronal migration
and distribution patterns, cell loss, low neuronal abundance, and

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Biomedicine - 14010019
microcephaly. Further effects shows that MeHg directly binds to tubulin and
inhibit microtubule formation, also disturb cell cycle progression
(cytoskeleton and mitotic spindles might be sensitive to MeHg).

Jessica Yohari Winata

Biomedicine - 14010019

References
Macherey, A., & Dansette, P. M. (2008). Biotransformations Leading to Toxic Metabolites:
Chemical Aspect, 674696.
National Research Council. (2000). Scientific Frontiers in Developmental Toxicology and
Risk Asesment [Online]. Available: https://www.nap.edu/read/9871/chapter/4 [2016,
Sept 23]. National Academy: Washington, DC.