Identification of the metabolites of episesamin in rat bile and human liver microsomes

Article abstract of DOI:10.1248/bpb.35.709

Episesamin is an isomer of sesamin, resulting from the refining process of non-roasted sesame seed oil. Episesamin has two methylendioxyphenyl groups on exo and endo faces of the bicyclic skeleton. The side methylendioxyphenyl group was metabolized by cyt

Full text of DOI:10.1248/bpb.35.709

May 2012
Regular Article
Biol. Pharm. Bull. 35(5) 709–716 (2012)
709
Identification of the Metabolites of Episesamin in Rat Bile and Human
Liver Microsomes
Namino Tomimori,* Masaaki Nakai, Yoshiko Ono, Yoshinori Kitagawa, Yoshinobu Kiso, and
Hiroshi Shibata
Institute for Health Care Science, Suntory Wellness Ltd.; 1–1–1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka
618–8503, Japan. Received December 18, 2011; accepted February 5, 2012; published online February 15, 2012
Episesamin is an isomer of sesamin, resulting from the refining process of non-roasted sesame seed
oil. Episesamin has two methylendioxyphenyl groups on exo and endo faces of the bicyclic skeleton. The
side methylendioxyphenyl group was metabolized by cytochrome-P450. Seven metabolites of episesamin
were found in rat bile after treatment with glucuronidase/arylsulfatase and were identified using NMR and
MS. The seven metabolites were (7α,7ꢀβ,8α,8ꢀα)-3,4-dihydroxy-3ꢀ,4ꢀ-methylenedioxy-7,9ꢀ:7ꢀ,9-diepoxylignane
(EC-1-1),
(7α,7ꢀβ,8α,8ꢀα)-3,4-methylenedioxy-3ꢀ,4ꢀ-dihydroxy-7,9ꢀ:7ꢀ,9-diepoxylignane
(EC-1-2)
and
(7α,7ꢀβ,8α,8ꢀα)-3,4:3ꢀ,4ꢀ-bis(dihydroxy)-7,9ꢀ:7ꢀ,9-diepoxylignane (EC-2), (7α,7ꢀβ,8α,8ꢀα)-3-methoxy-4-hydroxy-
3ꢀ,4ꢀ-methylenedioxy-7,9ꢀ:7ꢀ,9-diepoxylignane (EC-1m-1), (7α,7ꢀβ,8α,8ꢀα)-3,4-methylenedioxy-3ꢀ-methoxy-4ꢀ-
hydroxy-7,9ꢀ:7ꢀ,9-diepoxylignane (EC-1m-2), (7α,7ꢀβ,8α,8ꢀα)-3-methoxy-4-hydroxy-3ꢀ,4ꢀ-dihydroxy-7,9ꢀ:7ꢀ,9-
diepoxylignane (EC-2m-1) and (7α,7ꢀβ,8α,8ꢀα)-3,4-dihydroxy-3ꢀ-methoxy-4ꢀ-hydroxy-7,9ꢀ:7ꢀ,9-diepoxylignane
(EC-2m-2). EC-1-1, EC-1-2 and EC-2 were also identified as metabolites of episesamin in human liver micro-
somes. These results suggested that similar metabolic pathways of episesamin could be proposed in rats and
humans.
Key words episesamin; metabolite; cytochrome P450
Sesamin is a major lignan in sesame seeds and oil, and is
Nakai et al.3) have shown that sesamin was metabo-
partially epimerized to episesamin during the refining process lized to (1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-meth-
of non-roasted sesame seed oil.1) Epimerization to episesamin ylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-1) and
was also occurred under acid catalyzed conditions.2)
(1R,2S,5R,6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyc-
The mixture of sesamin and episesamin could be produced lo[3,3,0]octane (SC-2) through oxidization by demethylation
from refined sesame seed oil, and exhibits anti-oxidative by cytochrome P450.23,24) These compounds are further
activity,3–5) lowers serum cholesterol and lipid levels,6–10) de- methylated by catechol-O-methyltransferase (COMT) to
creases blood pressure,11–16) protects against alcohol-induced (1R,2S,5R,6S)-6-(4-hydroxy-3-methoxyphenyl)-2-(3,4-meth-
liver injuries,17) displays synergy with α-tocopherol,8,18,19) and ylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-1m) and
elevates γ-tocopherol in plasma and the liver.20,21) Ide et al.22) (1R,2S,5R,6S)-6-(4-hydroxy-3-methoxyphenyl)-2-(3,4-dihy-
reported that the change in the gene expression of hepatic fat- droxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-2m) (Fig. 1).
ty acid oxidation enzymes was greater with episesamin than Moazzami et al. demonstrated that the major urinary me-
with sesamin, and the differences in bioavailability appear to tabolite of sesamin was SC-1 and the excretion of SC-1 ranged
be important for their physiological activities.
from 22.2 to 38.6% in humans.25) A recent paper has shown
Fig. 1. Metabolic Pathways of Sesamin
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: Namino_Sugiura@suntory.co.jp
© 2012 The Pharmaceutical Society of Japan

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Vol. 35, No. 5
°
that CYP2C9 is the most important CYP (cytochrome) iso- (42.4mmol), and the mixture was heated at 70 C for 2h. After
form in the metabolism from sesamin to SC-1 in humans26)
cooling, the mixture was diluted with chlorobenzene (250mL)
however, little is known about the metabolites of episesamin and filtered through a Celite pad. The filtrate was washed with
in rats and humans. distilled water (3 times), dried with anhydrous sodium sulfate
;
In this study, metabolites of episesamin were isolated from and concentrated under reduced pressure to give a mixture
rat bile in vivo and from the reaction mixture with human (11.1g) of Epi-SAc-1-1, Epi-SAc-1-2 and Epi-SAc-2 as a pale
liver microsomes in vitro, and then their structures were de- yellow form.
termined to estimate the metabolic pathway of episesamin.
The resulting residue from the above procedure was treated
with 80% acetic acid (269mL) at room temperature for 15min.
After evaporation of the solvents, residual acetic acid was
removed by co-evaporation with water–ethanol (5 times), and
MATERIALS AND METHODS
Chemicals A sesame lignan fraction containing sesamin then with ethanol. The residue was purified by silica gel col-
and episesamin was prepared from refined sesame oil by crys- umn chromatography. Elution was performed with n-hexane–
tallization and silica gel chromatography as described previ- ethyl acetate (4:1 to 1:1, v/v) to obtain crude EC-1-1 and EC-
ously.1) Episesamin was purified from this fraction by HPLC 1-2. Elution was also performed with n-hexane–ethyl acetate
at an absorbance 280nm, using a 250mm×50mm i.d. Develo- (1:2 to ethyl acetate only, v/v) to give crude EC-2. The crude
sil ODS-UG-5 reversed-phase HPLC column (Nomura Chemi- EC-1-1 and EC-1-2 were purified by silica gel column chroma-
cal Co., Japan).3) Authentic standards of sesamin metabolites tography with n-hexane–ethyl acetate (4:1 to 1:1, v/v). EC-
(SC-1 and SC-2) were prepared according to the method of 1-1 was obtained as a yellow solid and EC-1-2 was obtained
Urata et al.27) by Nemoto Science Co., Ltd.
as a white solid. The EC-2 was purified by silica gel column
Enzyme Source β-Glucuronidase from Helix pomatia chromatography with n-hexane–ethyl acetate (1:1 to 1:2, v/v)
(Type H-2) was purchased from Sigma-Aldrich Japan (Osaka, and was obtained as a yellow solid.
Japan). Pooled human hepatic microsomes were purchased
from BD Gentest (Woburn, MA, U.S.A.).
Structural Determination of Metabolites of Episesamin
in Rat Bile Rats were fasted overnight with free access to
Animals Sprague Dawley (SD) rats, weighing 280–330g, water. The biliary duct of each rat was cannulated. Episesa-
were obtained from Oriental Bio Service (Kyoto, Japan). The min was suspended in olive oil and was orally administered
°
animals were maintained in an air-conditioned room at 24 C at a dose of 500mg/kg to rats. Bile was collected in a tube
°
with a 12h light/dark cycle. Drinking water and regular feed over 24h, and bile samples were stored in a −80 C freezer
were supplied ad libitum. The experiments were started after until needed. Bile samples were treated with β-glucuronidase/
the animals had been acclimatized for at least 1 week. Ex- arylsulfatase for hydrolysis, and extracted with ethyl acetate
perimental protocols were approved by the Animal Care and according to the method of Nakai et al.3) After concentra-
Use Committee of Suntory Holdings, Ltd., and followed the tion in vacuo, the resultant extract was dissolved in methanol
Guidelines for Animal Care and Use of Suntory Holdings, (MeOH) and then subjected to reversed-phase HPLC. The
Ltd.
Preparation
column was a Develosil ODS-UG-5 (250×20mm, 5µm). The
(7α,7′β,8α,8′α)-3,4-Dihydroxy-3′,4′- mobile phase consisted of (A) 0.05% aqueous trifluoroacetic
of
methylenedioxy-7,9′:7′,9-diepoxylignane (EC-1-1), (7α,7′β, acid (v/v) and (B) 0.05% trifluoroacetic acid/acetonitrile (v/v)
8α,8′α)-3,4-Methylenedioxy-3′,4′-dihydroxy-7,9′:7′,9- using a gradient elution of 0–100% B at 0–100min, and 100%
diepoxylignane (EC-1-2) and (7α,7′β,8α,8′α)-3,4:3′,4′- B at 100–110min. The flow rate was 5mL/min. Detection
Bis(dihydroxy)-7,9′:7′,9-diepoxylignane (EC-2) According wavelength was absorbance 280nm.
to the method of Urata et al.,27) EC-1-1, EC-1-2 and EC-2
Four colored fractions A to D were obtained and then
(metabolites of episesamin) were obtained by acid hydrolysis subjected to reversed-phase HPLC again. The column was a
subsequent to acetoxylation of episesamin (Chart 1).
Develosil C30-UG-5, (150×4.6mm, 5µm), the flow rate was
In detail, to a solution of episesamin (28.2mmol) and dry 1.0mL/min, and detection wavelength was absorbance 280nm.
chlorobenzene (282mL) was added lead (IV) tetraacetate The isocratic conditions for further purification of fractions
Chart 1. Acetoxylation and Acid Hydrolysis

May 2012
711
B, C and D were 34% MeOH, 55% MeOH and 60% MeOH, (EC-1-1, EC-1-2 and EC-2) Acetoxylated derivatives Epi-
respectively. SAc-1-1, Epi-SAc-1-2 and Epi-SAc-2 were given by acetox-
Metabolism of Sesamin or Episesamin with Human Liv- ylation of episesamin with Pb(OAc)4 in dry chlorobenzene.
er Microsomes Sesamin or episesamin (final conc. 100µM) After acid hydrolysis, crude fractions of EC-1 (3.6g) and EC-2
was added to a mixture of pooled human liver microsomes (2.1g) were obtained by silica gel column chromatography.
(0.5mg protein/mL), nicotinamide adenine dinucleotide phos- EC-1-1 (523mg, 5.4% from episesamin), EC-1-2 (518mg, 5.4%
phate (NADPH)-generating system (NADP 2.5mM, glucose- from episesamin) and EC-2 (334mg, 3.6% from episesamin)
6-phosphate 25mM, 2 units of glucose 6-phosphate dehydro- were isolated by further purification using silica gel column
genase, magnesium chloride 10mM), and 250mM potassium chromatography. The structure of EC-1-1, EC-1-2 and EC-2
1
phosphate buffer (pH7.4) containing 0.25mM ethylenediamine- was confirmed by mass and H-NMR spectra.
tetraacetic acid (EDTA) in a final volume of 0.5mL. The mix-
Identification of Metabolites of Episesamin in Rat Bile
°
tures were incubated at 37 C for 30min and then stopped by The episesamin-administrated rat bile extract was treated with
adding 0.5mL MeOH–acetonitrile (1:1, v/v). After centrifuga- glucuronidase/arylsulfatase and then subjected to reversed-
tion, the supernatant was filtered through a Millex-LH Filter phase HPLC. Four fractions were obtained as shown in Fig. 2.
(0.45mm; Millipore, Billerica, MA, U.S.A.) before analysis.
Metabolite 5 was isolated from fraction A. Metabolite 6 and
Spectroscopy The structures of the metabolites were 7, metabolite 1 and 2, metabolite 3 and 4 were purified from
“
assigned by nuclear magnetic resonance spectroscopy, incor- fractions B, C and D as described in Materials and Meth-
1
porating H-NMR, 13C-NMR, double quantum filtered correla- ods, respectively.
”
tion spectroscopy (DQF-COSY), total correlation spectroscopy
Seven metabolites of episesamin were identified in rat bile
(TOCSY), heteronuclear multiple bond correlation (HMBC), by MS and NMR. The molecular weights of the metabolites
heteronuclear single quantum coherence (HSQC), and nuclear were determinated as 342 (metabolites 1, 2), 356 (metabolites
Overhauser effect (NOE), rotating frame Overhauser effect 3, 4), 330 (metabolite 5) and 344 (metabolites 6, 7) by ESI-
(ROE). The NMR experiments were performed with a Bruker MS. The proton signal intensity of the methylenedioxy moiety
DMX-750 spectrometer (Bruker Biospin, Germany). Samples (–O–CH2–O–) in metabolites 1–4 was two protons at δ 6.0 by
were dissolved in DMSO-d6. The residual proton peak and 1H-NMR analysis. No proton signals of the methylenedioxy
1
1
13C peak of DMSO-d6 (δ 2.50 for H and δ 39.43 for 13C) were moiety in metabolites 5–7 were observed. The H- and 13C-
used as internal standard. The mass spectra were recorded NMR spectra of metabolites 3, 4, 6 and 7 showed a structure
with a Quattro micro MS system (Waters/Micromass, Man- containing one methoxy moiety by δ 3.75 or 3.76. The dif-
chester, U.K.), equipped with an electrospray ionization (ESI) ference of structures between metabolite 1 and 2, 3 and 4,
ion source. Cone voltage and capillary voltage was 15V and 6 and 7 were confirmed by NOE correlation of H-2 to H-8.
3.5kV, and source and desolvation temperatures were set at 80 The location of the methoxy group at carbon atom C-3 of me-
°
and 150 C, respectively.
tabolite 3 was confirmed by HMBC from the methoxy group
UPLC/MS Analysis of Metabolites The metabolites of to C-3, from 4-hydroxyl group to C-3, C-4, C-5. The rotating
sesamin and episesamin by human liver microsomes were frame Overhauser enhancement spectroscopy (ROESY) spec-
analyzed using ACQUITY ultra performance liquid chroma- trum further confirmed the structure, showing interactions
tography (UPLC) system (Waters Corp., Milford, MA, U.S.A.) between the methoxy group and H-2. Similarly, the location
coupled to a Quattro micro MS System. The column was an of the methoxy group at carbon atom C-3′ of metabolite 4 was
Acquity UPLC BHC C18, (100×2.1mm, 1.7µm, Waters Corp., confirmed by the HMBC from the methoxy group to C-3′,
°
Milford, MA, U.S.A.) maintained at a temperature of 40 C. NOE correlation between methoxy group and H-2′. The loca-
A constant flow rate of 0.25mL/min was used. The mobile tion of the methoxy group at carbon atom C-3 of metabolite 6
phase was composed of solvents A (10mM ammonium for- was confirmed by the HMBC from the methoxy group to C-3,
mate) and B (100% MeOH). The following gradient was used: NOE correlation between methoxy group and H-2. The loca-
0–0.5min: 80% solvent A/20% solvent B–65% solvent A/35% tion of the methoxy group at carbon atom C-3′ of metabolite 7
solvent B, 0.5–9min: 65% solvent A/35% solvent B–15% was confirmed by the HMBC from the methoxy group to C-3′,
solvent A/85% solvent B, and 9–10min, 15% solvent A/85% NOE correlation between methoxy group and H-2′.
solvent B. UV detection was carried out at 280nm.
The structures of metabolites 1–7 were identified by
To separate EC-1-1 and EC-1-2, the column used was a COSY, HSQC, HMBC, NOESY and ROESY experiments
COSMOSIL Cholester (100×2.0mm, 2.5µm, Nacalai Tesque
°
Co., Japan) maintained at a temperature of 40 C and with
a constant flow rate of 0.25mL/min. The mobile phase was
composed of solvents A (0.1% formic acid (v/v)) and B (100%
MeOH). Elution was performed with an isocratic solvent mix-
ture of 45% solvent A/55% solvent B.
The electrospray mass spectrometer was operated in nega-
tive ion mode. Cone voltage and capillary voltage was 45V
and 3.5kV, and source and desolvation temperatures were set
°
°
at 80 C and 250 C, respectively.
RESULTS
Fig. 2. HPLC Chromatogram of Rat Bile Extract after Treatment with
Glucuronidase/Arylsulfatase
Preparation of Authentic Metabolites of Episesamin

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Fig. 3. Structures of Metabolites of Episesamin
as follows: (7α,7′β,8α,8′α)-3,4-dihydroxy-3′,4′-methylenedioxy-
7,9′:7′,9-diepoxylignane (metabolite 1), (7α,7′β,8α,8′α)-3,4-
methylenedioxy-3′,4′-dihydroxy-7,9′:7′,9-diepoxylignane
(metabolite
methylenedioxy-7,9′:7′,9-diepoxylignane
2),
(7α,7′β,8α,8′α)-3-methoxy-4-hydroxy-3′,4′-
(metabolite 3),
(7α,7′β,8α,8′α)-3,4-methylenedioxy-3′-methoxy-4′-hydroxy-
7,9′:7′,9-diepoxylignane (metabolite 4), (7α,7′β,8α,8′α)-
3,4:3′,4′-bis(dihydroxy)-7,9′:7′,9-diepoxylignane
(metabolite
5), (7α,7′β,8α,8′α)-3-methoxy-4-hydroxy-3′,4′-dihydroxy-
7,9′:7′,9-diepoxylignane (metabolite 6) and (7α,7′β,8α,8′α)-
3,4-dihydroxy-3′-methoxy-4′-hydroxy-7,9′:7′,9-diepoxylignane
1
(metabolite 7). The H- and 13C-NMR spectral data of these
compounds are shown in Table 1. Metabolites 3 and 4 were
previously reported as xanthoxylol and pluviathilol.28–31) Ana-
lytical data of metabolite 5 was consistent with that reported
for the products of episesamin cultured with Aspergillus.32)
Metabolite 7 was previously reported as 3′-O-demethylepipin-
oresinol.33)
The structures of metabolites after treatment with gluc-
uronidase/arylsulfatase are shown in Fig. 3.
Identification of Metabolites of Episesamin by Human
Liver Microsomes A typical UV chromatogram after incu-
bation of sesamin or episesamin with human liver microsomes
is shown in Figs. 4a,b. Each metabolite peak (peak 1 or 2)
was detected. The negative ion LC/MS spectrum of peak 1 or
2 showed deprotonated molecular ion m/z 341 [M−H]− (Figs.
5a,b). HPLC retention time of peak 1 was identical to that of
the authentic standard SC-1 (Fig. 4c). HPLC retention time of
peak 2 was identical to those of the authentic standard EC-1-1
and EC-1-2 (Fig. 4c). To determine whether peak 2 is EC-1-1,
EC-1-2 or a mixture of the isomers, another HPLC was per-
Fig. 4. HPLC Chromatogram Comparison of the Authentic Standard
and the Metabolites of Sesamin or Episesamin
(a) Chromatogram after incubation of sesamin with human liver microsomes;
(b) chromatogram after incubation of episesamin with human liver microsomes;
(c) chromatogram of authentic standard SC2, EC-2, SC-1, EC-1-1, EC-1-2, sesamin
and episesamin.
formed. Peak 2 was separated into two peaks and the retention or episesamin with human liver microsomes; however, SC-2
time was identical to that of the authentic standard EC-1-1 or was detected as a metabolite of sesamin by human liver mi-
EC-1-2 (Figs. 6a,b). EC-1-1 and EC-1-2 were detected with crosomes with multiple reaction monitoring (MRM) at m/z
single ion recording (SIR) at m/z 341; therefore, peak 2 was 329.3>137.1, and the retention time was identical to that of
identified as a mixture of EC-1-1 and EC-1-2.
the authentic standard SC-2 (Fig. 7b). Similarly, EC-2 was de-
The other metabolites, except for SC-1 or EC-1, were not tected as a metabolite of episesamin (Fig. 7c).
detected on the UV chromatogram after incubation of sesamin

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Vol. 35, No. 5
Fig. 5. Negative Ion LC/MS Spectrum of the Ion m/z 341 [M−H]−
(a) Peak 1 metabolite of sesamin; (b) peak 2 metabolites of episesamin.
Fig. 7. MRM (m/z 329.3>137.1) Chromatogram of Comparison of the
Authentic Standard and the Metabolites of Sesamin or Episesamin
(a) Authentic standards SC-2 and EC-2; (b) chromatogram after incubation of
sesamin with human liver microsomes; (c) chromatogram after incubation of epis-
esamin with human liver microsomes.
humans. The predicted metabolic pathways of episesamin in
rats and humans are illustrated in Fig. 8.
Moazzami et al. demonstrated that the major urinary me-
tabolite of sesamin was SC-1 and the excretion of SC-1 ranged
from 22.2 to 38.6% in humans.25) Peñalvo et al. reported that
SC-1 and SC-2 were found after fermentation with human
microflora.34) Yasuda et al. have reported the contribution of
CYP1A2, 2C9, 2C19 and 2D6 to the metabolism of sesamin.
In particular, CYP2C9 was most important in the metabolism
from sesamin to SC-1 in humans.26) SC-2 were identified as
a metabolite of sesamin by human liver microsomes, but the
peak of SC-2 was not detected on the UV chromatogram. So
SC-2 is considered to be a minor metabolite in humans.
We demonstrated that SC-2 was formed by cytochrome
P450 in human liver microsomes. Presumably, SC-1 and SC-2
are generated first by cytochrome P450 in the small intestine
or the liver after absorption. Nakai et al.3) have shown that
Fig. 6. MS Chromatogram (SIR Mode at m/z 341) Comparison of the
Authentic Standard and the Metabolites of Episesamin
(a) Authentic standard EC-1-1 and EC-1-2; (b) chromatogram after incubation of
episesamin with human liver microsomes.
DISCUSSION
Episesamin has two methylendioxyphenyl these groups on SC-1 and SC-2 were further methylated by COMT to SC-1m
exo and endo faces, although sesamin has these groups on the and SC-2m in rats. After oral administration of a mixture
exo face of the bicyclic skeleton.2) Seven metabolites of epis- of sesamin and episesamin, we found sesamin, SC-1, SC-2,
esamin were found in rat bile after oral administration, and SC-1m, SC-2m, episesamin, EC-1, EC-2, EC-1m, EC-2m in
were identified by MS and NMR. Orally ingested episesamin human plasma (unpublished data). The metabolic pathway of
was oxidized to EC-1-1, EC-1-2 and EC-2 by demethylation sesamin is also considered to be similar in rats and humans.
by cytochrome P450,23,24) and EC-1-1, EC-1-2 and EC-2 were
EC-1 might be also responsible for pharmacological activ-
methylated by COMT into EC-1m-1, EC-1m-2, EC-2m-1 and ity, because SC-1 might be responsible for pharmacological
EC-2m-2, respectively. These metabolites were finally excret- activity such as anti-oxidative activity3) and enhancement of
ed into bile or blood by rapid conjugation of glucuronide by endothelium-dependent vasorelaxation13). The gene expression
UDP-glucuronosyltransferase or sulfation by sulfotransferase.
of hepatic fatty acid oxidation enzymes was more strongly up-
Similarly, episesamin was metabolized to EC-1-1, EC-1-2 regulated by episesamin than sesamin.22) The metabolism of
and EC-2 in human liver microsomes. Three metabolites of sesamin and/or episesamin might be related to various physi-
episesamin using human liver microsomes were identified by ological activities.
UPLC-MS/MS. No significant differences were observed in
This study clearly demonstrated that seven metabolites of
the yield of EC-1-1 and EC-1-2. As shown in Fig. 4b, EC-2 episesamin were isolated from rat bile, and that the metabo-
was not detected on the UV chromatogram, indicating that lites of episesamin by cytochrome P450 were also identified
EC-2 was a minor metabolite in humans. The metabolic using human liver microsomes. These results indicated that
pathway of episesamin is considered to be similar in rats and the metabolic pathway of episesamin is similar in rats and

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Fig. 8. The Predicted Metabolic Pathways of Episesamin in Rats and Humans
Atherosclerosis, 122, 135–136 (1996).
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