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© 2007 American Society for Nutrition J. Nutr. 137:940-944, April 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Quantitative NMR Analysis of a Sesamin Catechol Metabolite in Human Urine1

Ali A. Moazzami2,*, Rolf E. Andersson3 and Afaf Kamal-Eldin2

2 Department of Food Sciences and 3 Department of Chemistry, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden

* To whom correspondence should be addressed. E-mail: ali.moazzami{at}lmv.slu.se.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Sesamin, the major sesame oil lignan, is recognized for its health-promoting effects, including the lowering of cholesterol and elevation of {gamma}-tocopherol in rats and humans. However, little is known about the absorption and metabolism of sesamin in humans. In this study, 6 healthy volunteers took a single dose of sesame oil (508 µmol sesamin) and their urine was collected for four 12-h periods. The urine samples were treated with ß-glucuronidase/sulphatase and extracted with chloroform. The major urinary sesamin metabolite in the chloroform extract was collected using HPLC diode array detector and characterized as (1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane using NMR and mass spectroscopy. A quantitative 1H-NMR technique, based on the methylenedioxyphenyl protons signal ({delta} 5.91), was used for the quantification of the metabolite in the chloroform extracts of urine. The excretion of the sesamin catechol metabolite ranged from 22.2 to 38.6% (mean ± SD, 29.3 ± 5.6) of the ingested dose and happened mainly in the 1st 12 h after ingestion.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Sesame oil, known and used since ancient times, is unique for its content of 2 major lignans, sesamin and sesamolin (1). Sesamin, the most abundant lignan in sesame oil, has a range of bioactivities (2,3), e.g., the inhibition of absorption and biosynthesis of cholesterol resulting in the reduction of plasma and liver cholesterol in rats (4) and plasma cholesterol in humans (5,6) and the elevation of {gamma}-tocopherol in plasma and liver of rats (7) and in plasma of humans (8,9).

Recently, Penalvo et al. (10) demonstrated the conversion of sesamin to the mammalian lignans enterolactone (EL) and enterodiol (ED) in vitro and an increase in plasma EL and ED concentrations after the ingestion of sesame seeds by healthy humans. Other plant lignans, like secoisolariciresinol, matairesinol, lariciresinol and pinoresinol, are also converted to enterolactone and enterodiol (11,12) by the intestinal microflora of humans and animals (13–16). However, secoisolariciresinol diglucoside, the major lignan glucoside in flaxseed, causes an increase in liver cholesterol and a reduction in {alpha}- and {gamma}-tocopherols in the plasma and liver of rats, contrary to sesamin (7,17). The differences between the physiological effects of sesamin and those of secoisolariciresinol diglucoside, although both are converted to mammalian lignans by the intestinal microflora, indicate that sesamin exerts its effects through its intact molecule or different metabolic products. Nakai et al. (18) and Liu et al. (19) reported that sesamin undergoes cleavage of methylenedioxyphenyl (MDP)4 groups to catechol or methoxy catechol in vitro and in rats, respectively.

The aim of this study was to investigate the pattern of sesamin urinary metabolite(s) in humans and to develop and validate a new quantitative proton NMR spectroscopy (1H-NMR) method to analyze the main urinary metabolite after consuming a single dose of sesame oil incorporated in muffins.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Chemicals and reagents. Sesamin was kindly donated by Kalsec. Deuterated methanol (CD3OD) was purchased from Cambridge Isotope Laboratories. Chloroform and acetonitrile were purchased from Merck. They were of analytical grade and were used without further purification.

    Human studies. In a pilot study, one 30-y-old male maintained a diet low in lignans for 1 wk. At the end of this period, an overnight urine sample was collected and used as a control sample. The subject then consumed commercial sesamin capsules (Wuhu Tianyilubao) containing 310 µmol (110 mg) sesamin and 16 µmol (6 mg) sesamolin. Urine was collected for 24 h and used for the isolation of the sesamin metabolite.

In the main study, 6 healthy volunteers (3 women and 3 men, 22–32 y old) were selected among the staff members of the Department of Food Science (Swedish University of Agricultural Sciences). None of the subjects had undergone antibiotic treatment during the year preceding the study. Participants were requested to maintain a diet low in lignans for 1 wk prior to the sesame oil supplementation study. An informative sheet was provided with foods to be particularly avoided, including whole-grain products, seeds and nuts, legumes, beer and wine. The subjects were advised not to use pepper in their food in the week preceding the experiment, because pepper contains some compounds with the MDP group, e.g., piperine (20), which might interfere with the NMR quantification of sesamin urinary metabolite in this study. After this food-restriction period, control urine samples were collected overnight and the subjects were asked to consume 2 muffins (200 g) baked with virgin sesame oil and containing 508 µmol (180 mg) sesamin and 192 µmol (71 mg) of sesamolin. The urine was then collected for 48 h in four 12-h-intervals to determine the period of major excretion of sesame lignan metabolites. This study complied with the Helsinki Declaration, as revised in 1983. The volunteers agreed to participate after being informed of the experimental design and had the right to withdraw at any time.

    Extraction of metabolites in the urine. To a sample of urine (30 mL), 10 kU ß-glucuronidase/330 U sulphatase (Sigma, England) in 30 mL of 0.1 mol/L acetate buffer (pH = 5) was added and incubated for 24 h in a shaking water bath at 37°C to release any conjugated metabolites (21,22). These samples were then acidified to pH < 1 with 6 mol/L hydrochloric acid (considering higher recovery compared with pH 5 and 3), and extracted with 3 x 50 mL chloroform (considering higher recovery compared with ethyl acetate and solid phase extraction using C18). The chloroform extracts were pooled and a 20 mL portion was evaporated and dissolved in 0.5 mL of CD3OD or methanol for further analysis by NMR or HPLC, respectively. Each urine sample was deconjugated and extracted twice and each extract was analyzed twice by NMR or HPLC.

    High-performance liquid chromatography analysis and collection of metabolite. A sample analysis and collection of the major sesamin metabolite (~1.5 µmol) was performed by analytical HPLC (Dionex) equipped with an Econosil ODS column (5 µm, 250 x 4.6 mm; Alltech). The eluents used were 1) a 0.01 mol/L phosphate buffer (pH 2.8) containing 5% acetonitrile and 2) acetonitrile. Elution was performed as follows: 0–5 min (15% acetonitrile), 30 min (30% acetonitrile), and 40–50 min (70% acetonitrile) at a flow rate of 1.0 mL/min. Peaks were detected at 285 nm using a diode array detector (PDA-100), which also provided the spectra of the separated peaks. A peak (RT 37.5 min) (Fig. 1) was collected using the analytical HPLC and characterized by NMR and LC-MS.


Figure 1
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  		Figure 1  Typical reversed phase HPLC chromatogram of the chloroform extracts of deconjugated human urine.

 
    Characterization of the major sesamin metabolite. The structure of the sesame lignan metabolite collected by HPLC was assigned by nuclear magnetic resonance spectroscopy, incorporating 1H-NMR, correlation (COSY), total correlated (TOCSY), heteronuclear multiple bond correlation (HMBC), heteronuclear multiple quantum correlation (HSQC), and nuclear Overhauser effect (NOESY). The NMR experiments were performed with Bruker DRX 600. Measurements were taken at frequencies of 600 MHz (1H) and 199 MHz (13C) in 50 µL of CD3OD (D, 99.8%), using a 2 mm capillary in a microprobe head at 30°C. The 1H and 13C chemical shifts were referenced to the methyl signals from residual methanol; 1H ({delta} 3.31) and 13C ({delta} 49.0). A sequence with presaturation of the water peak was used for 1H-NMR. The mixing times for the different NMR techniques were as follow: TOCSY (60 ms), HMBC (65 ms), and NOESY (300 ms).

LC-MS (Agilent, 1100 series) equipped with electrospray ionization and Genesis C18 column (4.6 x 150 mm, 4 m particle size, Jones Chromatography) was used for further structural analysis of sesamin lignan metabolite. The eluents were: 1) 10 mmol/L acetic acid (pH 3) and 2) acetonitrile and were used as follows: 0–5 min (20% acetonitrile), 30–50 min (70% acetonitrile) at a flow rate of 0.4 mL/min. At the interface, the drying gas was set to 9 L/min, the nebulizer pressure was 30 psi, the drying gas temperature was 350°C, and the scanning range was 300–1000 m/z.

    Quantification of sesame lignan metabolites by NMR. The amount of the sesamin lignan metabolite in the chloroform extract of deconjugated urine from 6 subjects was quantified by NMR (Bruker DRX 400). Portions of the chloroform extracts (20 mL) were dried and dissolved in 0.5 mL of CD3OD for analysis by 1H-NMR. Signals corresponding to the MDP protons ({delta} 5.91) in the 1H-NMR spectra were used for the quantification of the metabolite using authentic sesamin solution in CD3OD as external standard. Because sesamin has 2 MDP groups in its molecule, it has twice the NMR response as its catechol metabolites in a similar molar solution (vide infra). The methyl group from residual methanol in CD3OD was used as internal standard and the ratio between the areas of MDP protons ({delta} 5.91) and the methyl group signal from residual methanol ({delta} 3.31) was used to draw the calibration curve.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Separation of the sesamin major lignan metabolite. Control urine and urine samples collected after sesamin intervention were incubated with deconjugating enzyme (ß-glucuronidase/sulphatase) or acetate buffer without enzyme, extracted with chloroform, and analyzed using HPLC. Comparision of the HPLC chromatograms of control and treatment urine samples in the pilot study revealed that peaks eluting at retention times (RT) 35–42 min appear just after deconjugation, which suggests their presence as conjugated metabolites in urine (Fig. 1). The chloroform extract of the deconjugated treatment urine possessed a peak (RT = 37.5 min), with characteristic UV spectrum of lignans ({lambda} Max = 234, 285 nm), which was not observed in the extract of deconjugated control urine. This peak was collected from the HPLC effluent and characterized by NMR and LC-MS.

    Structural characterization of the sesamin lignan metabolite isolated from human urine. 1H and 13C NMR spectral data of the isolated sesamin lignan metabolite isolated from human urine is represented in Table 1. H-1 ({delta} 3.11) appeared as a multiplet due to coupling with H-8a, H-8b, H-5 and H-2, whereas H-5 ({delta} 3.09) appeared as a multiplet due to coupling with H-4a, H-4b, H-1, and H-6, as confirmed by COSY. HMBC showed coupling between H-6'' ({delta} 6.84)/H-2'' ({delta} 6.87) and C-6 ({delta} 87.1). 1H-NMR showed meta-coupling between H-6'' and H-2'' (J = 1.5 Hz) and ortho-coupling between H-6'' and H-5'' (J = 8.1 Hz). The position of C-4'' ({delta} 148.7) was assigned from couplings with H-2'' ({delta} 6.87) and H-6'' ({delta} 6.84) and the positions of C-3'' ({delta} 148.7) and C-1'' ({delta} 136.2) were assigned from coupling with H-5'' ({delta} 6.77) in HMBC. Moreover, HMBC showed coupling between the MDP protons ({delta} 5.91) and C-4'' ({delta} 148.7), confirming the presence of the MDP group on this aromatic ring. On the other aromatic ring of the molecule, HMBC showed the couplings between H-6' ({delta} 6.69)/H-2' ({delta} 6.8) and C-2 ({delta} 87.1). 1H-NMR showed meta-coupling between H-6' and H-2' (J = 1.8 Hz) and ortho-coupling between H-6' and H-5' (J = 8.1 Hz). Position of C-4' ({delta} 145.7) was assigned from couplings with H-2' ({delta} 6.8) and H-6' ({delta} 6.69) and positions of C-3' ({delta} 146.4) and C-1' ({delta} 133.5) were assigned from couplings with H-5' ({delta} 6.74) in HMBC. The presence of hydroxyl groups on this aromatic ring caused upfield shifts in positions C-3' and C-4' and downfield shifts in positions C-2' and C-5' compared with the corresponding positions on the aromatic ring possessing the MDP group. The aromatic carbons were assigned from couplings to attached hydrogens in HSQC. The molecular weight of the isolated metabolite was corroborated using LC-MS, where it had a [M-H]– ion at m/z 341.2 with electrospray ionization. Thus, the structure of the sesamin metabolite was established as (1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane by NMR and MS (Fig. 2).


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  		TABLE 1 1H-NMR (600 MHz) and 13C-NMR (199 MHz) spectral data of the major sesamin urinary metabolite in humans

 

Figure 2
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  		Figure 2  Structures of (A) sesamin and (B) its urinary catechol metabolite, (1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane, quantified in this study.

 
    Validation of quantitative NMR technique. Experiments were performed to confirm that the signal corresponding to the MDP protons ({delta} 5.91) in 1H-NMR spectra of the urine extracts belong to the sesamin lignan metabolites. Comparison between 1H-NMR spectra of the extract of control urine and those of urine collected after sesamin intervention showed that the spectra contained MDP protons ({delta} 5.91) only after the intervention (Fig 3). Moreover, when the HPLC peak corresponding to the major sesamin metabolite was collected in a separate fraction (37–38 min; Fig 1), this fraction contained MDP protons ({delta} 5.91) in its NMR spectrum. The 2 other fractions collected between 0–37 min and between 38–70 min did not contain a signal at {delta} 5.91. This provided evidence that the MDP protons of the metabolite (RT 37.5 min), which was characterized in this study, account for the signal at {delta} 5.91 in the 1H-NMR spectrum of urine extracts.


Figure 3
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  		Figure 3  1H-NMR spectra of the chloroform extracts of control urine and treatment urine after ingestion of sesamin. Signals were marked to the corresponding position on the metabolite molecule. The ratio between methylenedioxyphenyl protons ({delta} 5.91) and residual methanol proton ({delta} 3.31) in the spectra was used for quantification of the metabolite in the extract against sesamin as standard.

 
The precision of the NMR method was determined by analyzing the sesamin lignan metabolite in a urine extract 6 times/d for 6 different days using the method described vide supra. The intra-assay precision (within 1-d variation) ranged from 1.3 to 2.0% with a mean of 1.6% and the inter-assay precision (between-days variation) was 1.6%.

The detection limit of the NMR method for the metabolite was determined to be 1.4 µmol/L of urine using a signal:noise ratio of 3, and the limit of quantification was determined as 5.6 µmol/L of urine using a signal:noise ration of 10. Linearity was confirmed between the lowest and highest concentrations of sesamin used in calibration curve (0.1–0.4 µmol sesamin dissolved in 0.5 mL CD3OD; Fig. 4). The sesamin equivalents of the metabolite in the urine extracts were determined using HPLC-DAD (285 nm) and the results were compared with the data obtained by the NMR method. The following correlation was obtained: Y = 1.16x + 11.48, R2 = 0.91 where, Y and X were the concentrations (mmol/L of urine) of the metabolite by NMR and HPLC, respectively.


Figure 4
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  		Figure 4  Calibration curve of the amount of sesamin in NMR tube (µmol) and 1H-NMR area of methylenedioxyphenyl (-O-CH2-O-) ({delta} 5.91) relative to the methyl signal of the residual methanol (0.5 mL CD3OD, {delta} 3.31). The entire experiment was done with the same CD3OD to have similar concentration of residual methanol.

 
    Urinary excretion of catechol metabolite. The urinary excretion of the sesamin catechol metabolite over four 12-h periods as quantified by the NMR technique, explained vide supra, is presented in Table 2. The majority of the sesamin metabolite was excreted during the first 12-h period even though subjects 2 and 4 continued the excretion of metabolite during the second 12-h period. For 3 subjects, trace amounts of the metabolite were detected in the third period, and no metabolite was detected in urine samples collected over the fourth period. The excretion of the sesamin catechol metabolite in urine ranged from 22.2 to 38.6% (29.3 ± 5.6%) of the ingested dose.


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  		TABLE 2 Urinary excretion of a sesamin catechol metabolite during four 12-h periods after consuming a single oral dose of 180 mg (508 µmol) sesamin12

 
No specific peak that could be assigned to a sesamolin metabolite or other sesamin metabolites was detected in the HPLC chromatograms or the NMR spectra. Moreover, no sesamin or sesamolin was detected by HPLC-DAD in urine samples, which is in agreement with Coulman et al. (23). Preliminary experiments showed that sesamolin may degrade under the acidic conditions of the stomach (data not shown). Investigation of NMR spectra showed that the identified catechol metabolite does not contain an oxygen atom between its furofuran and benzene rings. This structural differentiation confirms the lack of contribution for sesamolin, the second major lignan consumed in this study, to the production of the catechol metabolite.


   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, 29.3% of the ingested single dose of sesamin was excreted in subjects' urine in the form of catechol metabolite (Fig. 2). The fate of the rest of the dose is not clear at this time. It was previously shown that only ~0.1% of sesamin is absorbed through the lymph (4,24) and that >40% of orally ingested sesamin was excreted as metabolites in the bile in rats (18). It has also been shown that sesamin can be converted to enterolactone and enterodiol in humans (10,23). The total recovery of enterolactone and enterodiol after 4 wk ingestion of sesame seeds was reported as 14.9% of total seed lignans consumed by humans (23). In our study, only small amounts of enterolactone were detected in the HPLC chromatograms after a single dose intervention with sesame oil. Smeds et al. (25) showed that the conversion of plant lignans to enterolactone and enterodiol increases with longer intervention times, which may account for the low conversion of sesame oil lignans to enterolactone in our single-dose study.

Sesamin, like other lipophilic chemicals possessing MDP moiety, undergoes oxidative biotransformation and demethylation of its MDP group to form hydroxylated catechol metabolite (26). There is growing evidence that epithelial cells (enterocytes) of the human small intestine provide the first site for cytochrome P450 (CYP 450)-catalyzed metabolism of orally ingested compounds (27). It has also been proposed that high luminal concentrations of ingested compounds may lead to saturation of intestinal wall metabolism (28). Initially, the conjugation of phenolic compounds was thought to occur mainly in the liver, but phase II metabolism can also take place during uptake in the intestine (29). Investigation of the contents of sesamin, sesamin catechol metabolite, or conjugated sesamin metabolite in the portal vein after ingestion of sesamin may reveal information about the mechanism of absorption and also the contribution of intestinal metabolism and conjugation to the final excretion of the sesamin catechol metabolite. Moreover, a study of the possible efflux of sesamin, or its metabolite from enterocytes back to lumen by the ATP-binding cassette transporters, may provide more data for better understanding the amount of sesamin absorbed.

In this study, we did not detect the dicatechol metabolite previously identified in rats (18,19). It was shown that sesamin exerts an inhibitory effect on CYP-mediated catabolism of {gamma}-tocopherol in the liver (30). In this regard the formation of intermediate complexes with cytochrome is more extensive with MDP compounds that contain electron-donating substituents on their aromatic ring, whereas CO production is favored by electron-withdrawing substituents (31). The binding of the sesamin catechol metabolite to CYP 450 is possible when the metabolism of sesamin does not continue to promote oxidative demethylation of the second MDP group on the molecule after the formation of a catechol group in the first phenyl ring.

In this study, we did not observe a similar urinary metabolite of sesamolin, the other lignan in sesame oil. Preliminary results suggest that sesamolin decomposes under the pH conditions of the stomach (results not shown). Besides sesamin and sesamolin, sesame seeds are rich in lignan glucosides (32,33) but little is known about the metabolism and excretion of these other sesame seed lignans. Investigations of these are ongoing in our laboratory.


   FOOTNOTES
 
1 Supported by The Swedish Research Council (Vetenskapsrådet, project 621-2003-4746). Back

4 Abbreviations used: CD3OD, deuterated methanol; HMBC, heteronuclear multiple bond correlation; 1H, 600 MHz; 1H-NMR, proton NMR spectroscopy; HPLC-DAD, HPLC-diode array detector; MDP, methylenedioxyphenyl. Back

Manuscript received 15 October 2006. Initial review completed 15 November 2006. Revision accepted 17 January 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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