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Regulatory Toxicology and Pharmacology 83 (2017) 46e53

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Regulatory Toxicology and Pharmacology


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Chronic toxicity evaluation of Morinda citrifolia fruit and leaf in mice


Nor Aijratul Asikin Mohamad Shalan a, Noordin M. Mustapha b, Suhaila Mohamed a, *
a
UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, University Putra Malaysia, 43400 Serdang, Selangor, Malaysia
b
Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

a r t i c l e i n f o a b s t r a c t

Article history: Noni (Morinda citrifolia) leaf and fruit are used as food and medicine. This report compares the chronic
Received 9 June 2016 toxicity of Noni fruit and edible leaf water extracts (two doses each) in female mice. The 6 months study
Received in revised form showed the fruit extract produced chronic toxicity effects at the high dose of 2 mg/ml drinking water,
14 November 2016
evidenced through deteriorated liver histology (hepatocyte necrosis), reduced liver length, increased
Accepted 17 November 2016
Available online 18 November 2016
liver injury marker AST (aspartate aminotransferase) and albumin reduction, injury symptoms (hypo-
activity, excessive grooming, sunken eyes and hunched posture) and 40% mortality within 3 months. This
hepatotoxicity results support the six liver injury reports in humans which were linked to chronic noni
Keywords:
Morinda citrifolia
fruit juice consumption. Both doses of the leaf extracts demonstrated no observable toxicity. The hep-
Fruit atotoxicity effects of the M. citrifolia fruit extract in this study is unknown and may probably be due to
Leaf the anthraquinones in the seeds and skin, which had potent quinone reductase inducer activity that
Liver toxicity reportedly was 40 times more effective than l-sulforaphane. This report will add to current data on the
Mice chronic toxicity cases of Morinda citrifolia fruit. No report on the chronic toxicity of Morinda citrifolia fruit
Noni in animal model is available for comparison.
© 2016 Elsevier Inc. All rights reserved.

1. Introduction noni preparations in humans which has raised health concerns (Yu
et al., 2011), including hepatitis in M. citrifolia fruit juice products
Morinda citrifolia (family Rubiaceae), commonly known as Noni consumers (Stadlbauer et al., 2008). The association between the
in America and Mengkudu in Malaysia, as food and medicine has fruit juice products and hepatitis remains controversial, as no
been utilised by the Polynesians for over twenty centuries causal link was established between the liver injury cases and the
(Whistler, 1985). The roots, stems, bark, leaves, flowers, and fruits of juice consumption (European Food Safety Authority, 2006).
M. citrifolia plant are used in over 40 known recorded herbal A commercial source of M. citrifolia fruit juice from French Pol-
remedies in various combinations (Bruggnecate, 1992), for diabetes, ynesia was approved as a novel food by the European Union
high blood pressure, cancer, and many other illnesses (Abbott and (Europian Commission, 2003). Subsequent research concluded that
Shimazu, 1985), antibacterial (Natheer et al., 2012), antifungal and the regular intake of noni juice was not likely to cause any toxic
antihelmintic (Bhawna and Kumar, 2009), antioxidant (Siddiqui effects (European Food Safety Authority, 2006). In vitro hepato-
et al., 2014), anti-inflammatory (Basar et al., 2010), wound heal- toxicity and oral subchronic toxicity study reported that the noni
ing, anticancer effects (Wang and Su, 2001), anxiolytic (Kannan fruit juice is unlikely to induce adverse liver effects (West et al.,
et al., 2014), cardiovascular (Gilani et al., 2010), and immune 2009a,b). Analyses sponsored by Tahitian Noni, the main global
stimulation functions (Palu et al., 2008). noni juice provider, reported no toxicity from consumption of the
In the last decade, noni fermented and unfermented fruit juice, product (West et al., 2006, 2009a,b). A short term (28 days) double-
has become a widely traded dietary supplement globally, with blind clinical safety study, concluded that consuming up to 750 mL
health claims relating to some of its compounds, particularly the Tahitian Noni juice daily is safe (West et al., 2009a,b).
flavonoids (Deng et al., 2007; Takashima et al., 2007). Between The Morinda fruit and leaf were reportedly to contain various
2005 and 2011, there have been 7 reports on the hepatotoxicity of compounds (complete list given in Appendices) including acids
(Lindsay and Golden, 2012), alcohols, phenols, anthraquinone and
anthraquinone glycosides (Takashima et al., 2007), carotenoids,
esters (Zhang et al., 2014), flavonoids (Su et al., 2005), iridoids
* Corresponding author.
(Akihisa et al., 2010; Takashima et al., 2007), ketones and lactones
E-mail address: mohamed.suhaila@gmail.com (S. Mohamed).

http://dx.doi.org/10.1016/j.yrtph.2016.11.022
0273-2300/© 2016 Elsevier Inc. All rights reserved.
N.A.A. Mohamad Shalan et al. / Regulatory Toxicology and Pharmacology 83 (2017) 46e53 47

(Farine et al., 1996), lignans (Kamiya et al., 2004; Palu et al., 2008), 4. Results
nucleosides (Su et al., 2005), triterpenoids and sterols (Akihisa
et al., 2012; Takashima et al., 2007), and several minor com- The yield of the water extracts are 7.2 ± 0.5% for MCF and
pounds (Pak-Dek et al., 2011; Pawlus et al., 2005; Takashima et al., 4.5 ± 0.5% for MCL. Daily administration of MCL (1 and 2 mg/ml) for
2007). Scopoletin, a coumarin derivative, is suggested as a con- 6 months did not show any signs of toxicity or mortality. However,
stituent marker for M. citrifolia L. quality control (Samoylenko et al., the mice consuming MCF especially at 2 mg/ml water showed
2006). significant retarded body weight increase after the first month, as
Due to the controversial outcomes of M. citrifolia toxicity re- compared to the control mice (Fig. 1a). The liver weights and
ports, the current investigation aims to demonstrate the long term lengths, showed shrinkage in the 2 mg/ml MCF rats which was
effects of consuming M. citrifolia fruit and leaf aqueous extract in significant for the length but not for the liver weight when
female mice model. compared to control group (Table 1).
The mice on 2 mg MCF/ml showed 2 mortalities on day 68 and 93,
respectively, with obvious toxicity symptoms (Table 1), while those
2. Material and methods
on 1 mg MCF/ml water showed some liver histological changes.
Table 1 also shows the drinking water consumption, the calculated
Morinda citrifolia leaves (MCL) and fruit (MCF) were obtained
extract dosage and the equivalent human dose for the extract.
from the Institute of Bioscience (IBS), Universiti Putra Malaysia
The chronic consumption of M. citrifolia aqueous extract (MCL
(UPM). A voucher specimen SK2322/14 was deposited at the Lab-
and MCF at both concentrations) showed no significant changes in
oratory of Natural Products, IBS, UPM. M. citrifolia whole fruits and
the liver damage biomarker enzyme ALT, and serum creatinine
leaves were oven-dried at 45  C for 2 days, ground into powder and
levels, as compared to control group (Fig. 2). The normal ranges of
boiled in 1:10 w/v distilled water for 3 h, filtered and evaporated to
these biomarkers for mice are marked within the rectangle. The
dryness at 60  C to give an aqueous extract of fruits 7.21% and leaves
tissue injury biomarkers that were outside these ranges were only
4.51% w/w yield.
for AST (2 mg/ml MCL & MCF) and albumin (2 mg/ml MCF) which
The 6e7 weeks female Imprinting Control Region (ICR) mice
are indicative of liver and kidney injury respectively. The blood AST
were from the Faculty of Veterinary Medicine, UPM, and acclima-
increase indicated AST leakage from the injured hepatocyte mem-
tized for 7 days by housing and maintaining on a 12-h light/dark
brane. The decreased blood albumin levels indicated albumin loss
cycle at 25 ± 2  C. They were given standard pellet food (Gold Coins
via damaged renal tubules or glomeruli. However, there were sig-
from A Sapphire Enterprise, Serdang, Malaysia) and drinking water
nificant reductions in ALT levels, and urea levels (for the 1 mg MCL/
ad libitum. This study was approved by the lnstitutional Animal
ml, 2 mg MCL/ml, & 1 mg MCF/ml treated mice) compared to
Care and Use Committee, UPM, with approval number UPM/IACUC/
control mice, but they were still within the normal ranges. Any
AUP-R022/2013. The chronic toxicity was evaluated according to
values outside the normal range indicate either severe tissue
the OECD (Organisation for Economic Co-operation and Develop-
damage, membrane leakage, necrosis or hypertrophy.
ment) guideline 452 for female mice. Due to time and funding
Administration with both concentrations of MCL did not cause
budget limitation only females were used. Mice were then grouped
observable adverse effect on the hepatocytes histo-architecture
(n ¼ 5) into: A: Control (distilled drinking water DW); B: 1 mg MCL/
(Fig. 3). However, mice treated with the fruit extracts MCF (1 and
ml DW; C: 2 mg MCL/ml DW; D: 1 mg MCF/ml DW; and E: 2 mg
2 mg/ml) showed dose-dependent hepatocellular necrosis. The
MCF/ml DW. Animals were weighed weekly and observed for any
kidneys treated with both concentration of MCL and MCF showed
toxicity symptoms. At the end of the 6 months, all animals were
normal tubule structures (Fig. 4).
anaesthetized using ketamine (50 mg/kg) and xylazine (5 mg/kg)
and exsanguinated by cardiac puncture for blood and organ ex-
amination. The liver and kidneys were harvested, cleaned with 5. Discussion
saline, weighed and preserved for histopathology analysis.
Blood were collected into serum separation tube, allowed to clot Morinda citrifolia, or noni, is considered the second most
at room temperature for 30 min before centrifugation (5000 g for important medicinal plant in the Hawaiian Islands. The mice
15 min) for liver and kidney biomarker analysis: albumin, creati- consuming M. citrifolia leaves aqueous extract (MCL; 1 and 2 mg/
nine, and urea, alanine aminotransferase (ALT), aspartate amino- ml) did not show any observable toxicity effects and were consis-
transferase (AST), and alkaline phosphatase (ALP). tent with previous M. citrifolia leaves toxicity evaluations (Lagarto
Harvested tissues were fixed in buffered formaldehyde solution et al., 2013a,b; Serafini et al., 2011; West et al., 2007), although
(10%), dehydrated by serial ethanol solution, diaphonized with the AST values for the 2 mg/ml dose increased significantly above
ethanol-benzene and enclosed with paraffin. After processing, the the normal range after 6 months continuous daily consumption.
tissues were sectioned to a 4 mM thickness using a rotary micro-
tome and oven-dried overnight at 37  C. The sections were stained
with hematoxylin and eosin (H&E) and examined under compound
light microscope (40 magnifications).
All data are mean ± S.D, and significant differences between
groups were determined using one-way analysis of variance
(ANOVA), and further evaluated by Duncan's post hoc test and
considered significant at p < 0.05. All statistical analysis was per-
formed using SPSS 21.0 (SPSS Inc., Chicago, IL, USA).

3. Theory

Long term consumption of M. citrifolia fruit (MCF) or leaf (MCL) Fig. 1. Body weights of control and M. citrifolia aqueous extract treated mice after 6
aqueous extract at high or low dose may or may not damage months. Values are expressed as mean ± SD (n ¼ 5). Means with different superscript
mammalian tissues/organs and the possible cause for the injury. letters within the same graph are significantly different (p < 0.05).
48 N.A.A. Mohamad Shalan et al. / Regulatory Toxicology and Pharmacology 83 (2017) 46e53

Table 1
Chronic toxicity evaluation of Morinda citrifolia aqueous extract administered in drinking water.

Group Control MCL (1 mg/ml) MCL (2 mg/ml) MCF (1 mg/ml) MCF (2 mg/ml)

% Mortality 0 0 0 0 40
Days after consumption before Mortality e e e e 67 and 92
Toxicity symptoms None None None None Hypoactivity, excessive grooming,
sunken eyes, hunched back
Drinking water intake (ml/day) 6.0 ± 0.5a 4.1 ± 0.5b 3.2 ± 0.8bc 4.1 ± 0.9bc 2.9 ± 0.3c
Dose (mg extract/kg/day 0 142 ± 13 225 ± 25 142 ± 9 241 ± 5
Equivalent human dose (mg extract/kg/day) 0 11.5 ± 1 18 ± 2 11.5 ± 1 20 ± 1
Liver weight (mg) 1.6 ± 0.3a 1.6 ± 0.6a 2.1 ± 0.4a 1.8 ± 0.4a 1.5 ± 0.8a
Liver length (mm) 27.7 ± 0.3b 28.1 ± 1.3b 29.1 ± 1.7b 28.1 ± 1.6b 24.6 ± 2.1a

All treated mice were observed for any signs of toxicity (behavioral changes and mortality) for 6 months.
Values are expressed as mean ± SD (n ¼ 3). Means with different superscript letters within the same graph are significantly different (p < 0.05).

Fig. 2. (A) Liver and Kidney damage biomarkers in mice from chronic administration of M. citrifolia aqueous fruit (MCF) and leaf (MCL) extract. Liver injury biomarkers [A: alanine
aminotransferase (ALT), B: aspartate aminotranferase (AST), C: alkaline phosphatase (ALP)]; Kidney injury biomarkers [D: albumin, E: creatinine, F: urea]. Areas within the dark lines
indicate the normal ranges for mice (www.ahc.umn.edu/rar/refvalues.html). Values are expressed as mean ± SD (n ¼ 3).
N.A.A. Mohamad Shalan et al. / Regulatory Toxicology and Pharmacology 83 (2017) 46e53 49

Fig. 3. Histopathology of the liver hepatocytes at autopsy.

However, mice consuming M. citrifolia fruit aqueous extract 100e200 mg extract/kg mice body weight. This dose is the Human
(especially at 2 mg MCF/ml) showed significant differences in body Equivalent dose of 8e16 mg/kg body weight, or 0.5e1 g for a hu-
weights compared to the others, and obvious toxicity symptoms man weighing around 60 kg. A human drinking 2 L of tea daily,
(hypoactivity, excessive grooming, sunken eyes and hunched would consume about 1e2 g of tea extract depending on the
posture) and 40% mortality within 3 months. Toxicity biomarker strength, assuming a 200 ml cup of tea contains 2 g of tea leaf.
analysis from the 2 mg MCF/ml DW mice showed significant The main health concerns were the probable content of carci-
changes for blood albumin and AST together with positive liver nogenic anthraquinones, in particular alizarin, rubiadin, and lucidin
necrosis. These data supports the reports that chronic consumption in noni. The US National Toxicology Program investigations
of MCF aqueous extract may cause hepatotoxicity. The low dose concluded that anthraquinones can cause cancer of the liver, kidney,
MCF (1 mg MCF/ml) showed some liver necrosis but was not urinary bladder, and thyroid in rats and mice (National Toxicology
enough to cause any mortality. Autopsy was done on the dead mice Program, 2005). Animal reports on anthraquinones in madder
and showed that the main cause of death was hepatotoxicity as roots (Rubia tinctorum, Rubiaceae) showed possible genotoxic and
shown in Fig. 3. There was no observable injury in the other organs carcinogenic effects (Inoue et al., 2009). The M. citrifolia fruit extract
such as the kidney (Fig. 4). encompass the flesh, seed and skin. Noni fruit puree from which the
The 1e2 mg/ml dose chosen for the study is equivalent to seeds and skin fragments had been removed had no detectable
50 N.A.A. Mohamad Shalan et al. / Regulatory Toxicology and Pharmacology 83 (2017) 46e53

Fig. 4. Histopathology of the kidney tubules at autopsy.

amount of anthraquinones, as reported in the anthraquinone con- (Bussmann et al., 2013). The 2-methoxy-1,3,6-
tents of various different noni products and preparations trihydroxyanthraquinone which were isolated from noni fruit
N.A.A. Mohamad Shalan et al. / Regulatory Toxicology and Pharmacology 83 (2017) 46e53 51

MeOH extract, showed almost 40 times more potent quinone rats consumed 1000 mg extract/kg/day for 28 days, for sub-acute
reductase inducer activity than l-sulforaphane, and without obvious toxicity, and (iv) Wistar rats ingested 100, 300, and 1000 mg/kg
in vitro cytotoxicity (Pawlus et al., 2005). Reduction of electrophilic for 90 days for subchronic toxicity. Genotoxicity and short-term
quinones by quinone reductase is an important detoxification toxicity test showed no toxicity at 500e2000 mg/kg doses. Signif-
pathway; and quinone reductase induction has been proposed as a icant changes occurred in hemoglobin, and differential leukocyte
marker for cancer chemoprevention (Cuendet et al., 2006). Hence, count after subchronic dosing, but no histological abnormalities
in the present study and due to the assumed presence of the 2- were observed, that were outside the normal range or irreversible.
methoxy-1,3,6-trihydroxyanthraquinone in the examined extract, The young leaf is often used as vegetable or salad by the natives,
there was no observable neoplastic lesion or preneoplastic lesions in and have never been reported for any adverse toxicity. To the best of
any of the autopsied tissues. However chronic long term in vivo our knowledge there is currently no animal chronic toxicity study
consumption may produce hepatotoxic effects as observed here. report on Noni fruit. This report will add to the existing data on the
The hepatotoxic effects of the M. citrifolia fruit extract in this study chronic toxicity of Morinda citrifolia fruit.
(at 2 mg/ml dose) is yet to be confirmed whether they are caused by
the anthraquinones or other essentially still unknown compounds, 6. Conclusions
and further research need to be conducted.
The 7 hepatotoxicity reports between 2005 and 2011, were from Chronic consumption of M. citrifolia fruit aqueous extract
consuming Noni tea or product (2 cases), Noni juice (4 cases) and an especially at high doses may cause hepatotoxicity, weight loss and
energy drink (1 case). The early report described (i) a young man eventual mortality, but chronic consumption of M. citrifolia leaves
(aged 29) with prior hepatitis due to small paracetamol medication, aqueous extract (1 and 2 mg/ml) produced no observable toxic
developed liver failure after drinking 1.5 l Tahitian noni juice over effects, consistent with previous M. citrifolia leaves toxicity reports.
three weeks (and for 9 days prior to admission, approximately 7 g/
d of a Chinese herbal mix containing bupleuri, pinellia, scutellaria,
codonopsis, glycyrrhizae, schizonepeta, and paeonia), and (ii) an Declaration of conflicting interests
older woman (aged 62) with no previous liver toxicity developed
acute hepatitis after consuming 2 L noni juice over 3 months Nor Aijratul Asikin Mohamad Shalan, Noordin Mustapha, and
(Stadlbauer et al., 2005). The liver function tests improved soon Suhaila Mohamed declare that we have no conflict of interest.
after stopping Noni fruit product consumption (Stadlbauer et al.,
2008). Large consumption of the fruit reportedly caused abortion Acknowledgement
and Noni root bark are traditionally used as an abortifacient
(Pilkington, 2015). This study is supported by the Herbal Development Office,
Traditional folk medicine knowledge in Malaysia, recommended Ministry of Agriculture of Malaysia (Grant number: NH0513S009).
that the fruit is only consumed at most one fruit a week. M. citrifolia
leaf on the other hand, reportedly has antioxidant, liver-protective
Transparency document
and wound restorative effects without any acute, sub-acute and
sub-chronic oral toxicity, with an oral intake of 1000 mg/kg of
Transparency document related to this article can be found
M. citrifolia leaf ethanolic extract as the no observed-adverse-effect
online at http://dx.doi.org/10.1016/j.yrtph.2016.11.022.
level (NOAEL) (Lagarto et al., 2013a,b). In that toxicity study on the
leaf extract, (i) the micronuclei frequency in rodents bone marrow
cells were measured for genotoxicity, (ii) animals received 500, Appendices
1000, and 2000 mg/kg extract for acute toxicity, (iii) both gender
A. Anthraquinone content in Noni samples (Bussmann et al., 2013)

Table 2
Anthraquinone content in Noni samples.

Sample ID Lucidin 269/251 Total alizarin mg/kg Purpurin 255/227 Rubiadin 253/225

Sample_±1 / / / / Fresh noni seedless pulp, no skin


Sample_±2 / / / / Fresh noni seeded pulp, no skin
Sample_±3 / 0.152 / Detectable Fermented noni fruits
Sample_±4 / / / / Noni powder, seedless, and no skin
Sample_±5 / 0.279 / Detectable Ripe noni dried
Sample_±6 Detectable 0.337 / / Overripe noni dried
Sample_±7 / 0.781 / / Noni powder
Sample_±8 Detectable 0.334 / / Noni powder (unfermented)
Sample_±9 Detectable 4.655 / Detectable Noni powder (fermented)
Sample_±10 Detectable 0.365 / Detectable Noni powder
Sample_±11 Detectable 7.797 / Detectable Noni powder (fermented)
Sample_±12 Detectable 0.774 / / Noni powder
Sample_±13 Detectable / / / Noni powder
Sample_±14 / 8.612 / Detectable Noni powder (Peru)
Sample_±15 Detectable 0.725 / Detectable Noni powder
Sample_±16 Detectable 0.677 / Detectable Noni powder
Sample_±17 / / / / Juice, seedless, and no skin
Sample_±18 / / / / Juice, seedless, and no skin
Sample_±19 / 0.053 / Detectable Noni juice
Sample_±20 / / / / Noni juice, seedless, and no skin
Sample_±21 / 0.281 / Detectable Noni leaf tincture
Sample_±22 / / / / Noni tonic
Sample_±23 / / / / Maca/Cordia powder (comparison)
Sample_±24 / / / / Chilchos coffee (for comparison)
52 N.A.A. Mohamad Shalan et al. / Regulatory Toxicology and Pharmacology 83 (2017) 46e53

B. Compounds in Morinda citrifolia leaf: nose; 1-Palmitin; 2-Heptanone; 2-Methylbutanoic acid; 2-


Methylpropanoic acid; 2-O-(b-D-glucopyranosyl)-1-O-hexanoyl-
Alanine; Arginine; Aspartic acid; Asperuloside; Asperulosidic b-D-gluropyranose; 2-O-(b-D-glucopyranosyl)-1-O-octanoyl-b-D-
acid; Aucubin; Barbinervic acid; Benzaldehyde; Benzeneacetalde- gluropyranose; 2,6-di-O-(b-D-glucopyranosyl)-1-O-hexanoyl-b-D-
hyde; Campesta-5,7,22-trien-3b-ol; Campesterol; Citrifolinin A; glucopyranose; 2,6-di-O-(b-D-glucopyranosyl)-1-O-octanoyl-b-D-
Citrifolinin A-1; Citrifolinin Ba; Citrifolinin Bb; Citrifolinoside A; glucopyranose; 2-Methoxy-1,3,6-trihydroxyanthraquinone; 2-
Citrifolinoside B; Citrifoside; Clethric acid; Cycloartenol; Cysteine; Methyl-3,5,6-trihydroxyanthraquinone; 2-Methyl-3,5,6-trihydro-
Cystine; Deacetyl asperuloside; Deacetylasperulosidic acid (DAA); xyanthraquinone 6-O-b-D-xylopyranosyl-(1e6)-b-D-glucopyrano-
E-Phytol; Epicatechin; Geranyl acetone; Glutamic acid; Glycine; side; 3,30 -Bisdemethylpinoresinol; 3,30 -Bisdemethyltanegool; 3-
Hederagenin; Histidine; Isoleucine; Kaempferol; Kaempferol-3-O- Hydroxy-2-butanone; 3-Hydroxymorindone; 3-Hydroxym-
a-l-rhamnopyranosyl-(1e6)-b-d-glucopyranoside Kaempferol 3-O- orindone 6-O-b-D-xylopyranosyl-(1e6)-b-D-glucopyranoside; 3-
b-D-glucopyranosyl-(1 / 2)-a-Lrhamnopyranosyl-(1 / 6)-b-D- Methyl-2-buten-1-ol; 3-Methyl-3-buten-1-ol; 3-Methylbut-3-
galactopyranoside; Ketosteroids stigmasta-4-en-3-one; Leucine; enyl-b-D-glucopyranose; 3-Methylbut-3-enyl-6-O-b-D-glucopyr-
Linoleic acid; Lucidin; Lucidin 3-O-b-Dxylopyranosyl-(1e6)-b-D- anosyl-b-D-glucopyranose; 3-Methylthiopropanoic acid; 3,19-
glucopyranoside; Methionine; Methyl oleate; Methyl pheophorbide Dihydroxyursolic acid; 4-epi-Borreriagenin; 4-Hydroxy-3-methox-
a; Methyl pheophorbide b; Methyl plamitate; Nicotifloroside; Ole- ycinnamaldehyde; 5,6-Dihydroxylucidin; 5,6-Dihydorxylucidin 3-
anolic acid; oxalic acid; Palmitic acid; Peucedanocoumarin III; O-b-D-xylopyranosyl-(1e6)-b-D-glucopyranoside; 5,15-Dime-
Phenylalanine; Pheophorbide a; Phytic acid; Phytol; Proline; Pter- thylmorindol; 5,15-di-O-Methyl morindol; 5,15-DMM; 6a-
yxin; Quercetin; Quercetin-3-O-a-L-rhamnopyranosyl-(1 / 6)-b- Hydroxyadoxoside; 6b,7b-Epoxy-8-epi-splendoside; 6-Hydrox-
d-glucopyranoside; Quercetin 3-O-b-D-glucopyranoside; Quercetin yanthragallol-1,3-di-O-methyl ether; 6-O-(b-D-glucopyranosyl)-1-
3-O-b-D-glucopyranosyl-(1 / 2)-a-Lrhamnopyranosyl-(1 / 6)-b- O-hexanoyl-b-D-glucopyranose; 6-O-(b-D-glucopyranosyl)-1-O-
D-galactopyranoside; Roseoside II; Rotungenic acid; Rutin; Scopo- octanoyl-b-D-glucopyranose; 19a-Methylursolic acid; Acetic acid;
letin; Serine; Stigmasta-4-22-dien-3-one; Stigmasta-4-en-3-one; Americanin A; Americanoic acid; Americanol A; Anthragallol 1,3-
Stigmasterol; Tannic acid; Threonine; Triterpene cycloartenol; di-O-methyl ether; Anthragallol 2-methyl ether; Austrocortinin;
Tryptophan; Tyrosine; Ursolic acid; and Valine; D5,7 Sterol cam- Ascorbic acid; Asperuloside; Asperulosidic acid; Asperulosidic acid
pesta-5,7,22-trien-3b-ol; D5 Sterols b-sitosterol; b-Sitosterol; (þ) methyl ester; Asperuloside tetraacetate; Aucubin; Balanophonin;
Catechin; b-Carotene; b-Ionone; a-Ionone; 1,2-Dihydro-1,1,6- Benzoic acid; Benzyl alcohol; Borreriagenin (previously mor-
trimethyl-naphthalene; 1,5,15-Trimethylmorindol; 2-Methyl-3,5,6- indacin); Butanoic acid; Caproic acid; Caprylic acid; Cytidine;
trihydroxyanthraquinone; 2,6,10,14,18,22-Tetracosahexaene; 2- Deacetylasperuloside; Deacetylasperulosidic acid; Deacetylasper-
Methyl-3,5,6-trihydroxyanthraquinone-6-O-b-D-xylopyranosyl- ulosidic acid methyl ester; Decanoic acid; Dehydro-
(1e6)-b-D-glucopyranoside; 3-Hydroxymorindone 6-O-b-D-xylo- methoxygaertneroside; (E)-6-Dodeceno-g-lactone; Elaidic acid;
pyranosyl-(1e6)-b-D-glucopyranoside; 3-Hydroxymorindone; Epicatechin; Ethyl caproate; Ethyl caprylate; Ethyl decanoate; Ethyl
5,15-Dimethylmorindol; 3-O-Acetylpomolic acid; 4-(30 (R)-Hydrox- hexanoate; Ethyl octanoate; Ethyl palmitate; (Ethylthiomethyl)
ybutyl)-3,5,5,trimethyl-cyclohex-2-en-1-one; 5,6-Dihydroxylu- benzene; Eugenol; Heptanoic acid; Hexanamide; Hexanedioic acid;
cidin; 5,6-Dihydorxylucidin 3-O-b-D-xylopyranosyl-(1e6)-b-D- Hexanoic acid; Isoprincepin; Isoscopoletin; Kaempferol; Lauric
glucopyranoside; 5,15-DMM; 5-Methylfurfural; 5-Benzofuran car- acid; Limonene; Linoleic acid; Lucidin; Lucidin 3-O-b-Dxylopyr-
boxylic acid-6-formyl methyl ester; 6,10,14-Trimethyl-2- anosyl-(1e6)-b-D-glucopyranoside; Methyl a-D-fructofuranoside;
pentadecanone; 13-Epi-phaeophorbide a methyl ester; 13- Methyl b-D-fructofuranoside; Methyl 3-methylthio-propanoate;
Hydroxy-9,11,15-octadecatrienoic acid; 132(R)-Hydroxypheoph- Methyl decanoate; Methyl elaidate; Methyl hexanoate; Methyl
orbide a methyl ester; 13(S)-Hydroxypheophorbide a methyl ester; octanoate; Methyl oleate; and Methyl palmitate (Deng et al., 2010).
151(R)-Hydroxypurpurin-7 lactone dimethyl ester; 15(S)-Hydrox-
ypurpurin-7 lactone dimethyl ester; (Deng et al., 2011; West and
Zhou, 2008). Flavonoids such as Kaempferols are reportedly can- References
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