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Chem. Pharm. Bull. 51(4) 378—384 (2003) Vol 378 Chem. Pharm. Bull. 51(4) 378—384 (2003) Vol. 51, No. 4 Transformation of Arctiin to Estrogenic and Antiestrogenic Substances by Human Intestinal Bacteria a a b a Li-Hua XIE, Eun-Mi AHN, Teruaki AKAO, Atef Abdel-Monem ABDEL-HAFEZ, a ,a Norio NAKAMURA, and Masao HATTORI* a Institute of Natural Medicine, Toyama Medical and Pharmaceutical University; 2630 Sugitani, Toyama 930–0194, Japan: and b Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University; 2630 Sugitani, Toyama 930–0194, Japan. Received October 23, 2002; accepted January 18, 2003 After anaerobic incubation of arctiin (1) from the seeds of Arctium lappa with a human fecal suspension, six -metabolites were formed, and their structures were identified as (؊)-arctigenin (2), (2R,3R)-2-(3؅,4؅-dihydroxy -(benzyl)-3-(3؆,4؆-dimethoxybenzyl)butyrolactone (3), (2R,3R)-2-(3؅-hydroxybenzyl)-3-(3؆,4؆-dimethoxybenzyl butyrolactone (4), (2R,3R)-2-(3؅-hydroxybenzyl)-3-(3؆-hydroxy-4؆-methoxybenzyl)butyrolactone (5), (2R,3R)-2- -3؅-hydroxybenzyl)-3-(3؆,4؆-dihydroxybenzyl)butyrolactone (6), and (؊)-enterolactone (7) by various spectro) scopic means including two dimensional (2D)-NMR, mass spectrometry, and circular dichroism. A possible metabolic pathway was proposed on the basis of their structures and the time course of the transformation. En- terolactones obtained from the biotransformation of arctiin and secoisolariciresinol diglucoside (SDG, from the (seeds of Linum usitatissium) by human intestinal bacteria were proved to be enantiomers, with the (؊)-(2R,3R and (؉)-(2S,3S) configurations, respectively. Compound 6 showed the most potent proliferative effect on the growth of MCF-7 human breast cancer cells in culture among 1 and six metabolites, while it showed inhibitory activity on estradiol-mediated proliferation of MCF-7 cells at a concentration of 10 mM. These results indicate that the transformation of 1 by intestinal flora might be essential for the manifestation of the estrogenic and antiestrogenic activity of 1. Key words arctiin; human intestinal bacteria; enterolactone; mammalian lignan; MCF-7 cell; phytoestrogen In 1980, two lignan compounds, enterodiol and enterolac- Results tone, were reported from human and animal species.1) They Transformation of Arctiin (1) by Human Intestinal were given the name mammalian lignans, because unlike Flora After anaerobic incubation of arctiin (1) with a bac- plant lignans they carry phenolic hydroxy groups only in the terial mixture of human feces, the culture was extracted with meta position of the aromatic ring and they were assumed to acidified n-BuOH and the extract was subjected to Diaion play an important role in the prevention of hormone-depen- HP-20, Sephadex LH-20, silica gel, and RP-18 column chro- dent diseases, such as breast cancer and prostate cancer.1—3) matography. Six metabolites (2—7) (Fig. 1) were isolated The origins of enterodiol and enterolactone were later found and identified by electron impact mass (EI-MS), one dimen- to be plant lignans, such as secoisolariciresinol and sional (1D) and two dimensional (2D)-NMR, and circular matairesinol, in vegetarian food, and to be transformed by dichroic (CD) spectroscopy. gut microflora in the proximal colon.4,5) As enterodiol and Compound 2 was detected as the first metabolite from 1 by enterolactone are similar in partial structure to estradiol, they thin-layer chromatography (TLC). The EI-MS showed a mol- were expected to have estrogenic or antiestrogenic activity ecular ion peak at m/z 372, 162 mass units (C6H10O5) less and so far to influence hormone-dependent diseases.6—8) Re- than that of 1. The 1H- (see Experimental) and 13C-NMR cently, arctiin, which is a glycoside of arctigenin and abun- dant in the seeds of Arctium lappa, was reported to show a protective effect against 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine (PhIP)-induced mammary carcinogensis in female rats with oral administration.9) Arctiin was shown to be transformed to two metabolites (arctigenin and AM2) by rat intestinal flora.10) The transformation of secoisolariciresinol diglucoside (SDG) to enterodiol and enterolactone by human intestinal bacteria was studied in our department, and two bacterial strains, Peptostreptococcus sp. SDG-1 and Eubacterium sp. SDG-2, responsible for the conversion of SDG were isolated.11) Knowing the differences in bacterial species and their numbers between human and rat intestinal flora, we as- sumed that the respective transformations of arctiin (1) would be different. In the present paper, we report the trans- formation of 1 by human intestinal bacteria and the influence of its metabolites on the growth of human breast cancer MCF-7 cells. Fig. 1. Structures of Arctiin (1) and Its Metabolites (2—7) * To whom correspondence should be addressed. e-mail: [email protected] © 2003 Pharmaceutical Society of Japan April 2003 379 spectra (Table 1) were in good agreement with those reported 12.2, 14.6, and 8.9 ppm, respectively, compared with those of for (2R,3R)-(Ϫ)-arctigenin.12) 3, which indicated that dehydroxylation had occurred in the The 1H-NMR spectrum of compound 3 showed two para position. Compound 4 also showed negative Cotton ef- methoxy signals in contrast with the three methoxy signals of fects around 280 and 231 nm. The structure of 4 was conse- 2. Therefore 3 was assumed to be a demethylation product of quently concluded to be (2R,3R)-2-(3Ј-hydroxybenzyl)-3- 2. This was confirmed by the presence of a molecular ion (3Љ,4Љ-dimethoxybenzyl)butyrolactone. The racemic com- peak at m/z 358 in the EI-MS spectrum and 13C-NMR spec- pounds of 4 were previously synthesized by Eich et al.14) ϩ tral evidence (two methoxy signals, d C 56.0, 55.9, Table 1). The molecular ion peak of compound 5 (m/z 328 [M] ) in The CD spectrum of 3 showed two negative Cotton effects the EI-MS spectrum was 14 mass units (CH2) less than that around 282 and 233 nm, similar to that reported for (2R,3R)- of 4, indicating that 5 is a demethylation product of 4. Proton 2,3-dibenzylbutyrolactone.13) The 1H- and 13C-NMR spectral and carbon NMR signals due to a 3Ј-hydroxybenzyl group data agreed with those of a metabolite of arctiin (1) trans- were almost the same as those of 4, while signals due to a formed by rat intestinal flora.10) The structure of 3 was thus methoxyl-bearing benzyl group were changed; a signal of C- determined to be (2R,3R)-2-(3Ј,4Ј-dihydroxybenzyl)-3- 3Љ was shifted upfield by 3.5 ppm, while that of C-2Љ was (3Љ,4Љ-dimethoxybenzyl)butyrolactone. shifted downfield by 2.8 ppm, indicating that demethylation Compound 4 showed a molecular ion peak at m/z 342 in had occurred at C-3Љ in the 3Љ,4Љ-dimethoxyphenyl ring sys- its EI-MS spectrum, 16 mass units less than that of 3, sug- tem. This was further confirmed by the heteronuclear multi- gesting that 4 is a dehydroxylation product of 3. This was ple-bond coherence (HMBC) experiment; a signal of C-4Љ further confirmed by the presence of an additional aromatic showed correlations to proton signals of MeO-4Љ, H-2Љ, and proton signal at d 6.70 in the 1H-NMR spectrum. In the 13C- H-6Љ (Fig. 2). The CD spectrum of 5 showed negative Cotton NMR spectrum, a C-4Ј signal appeared upfield by 28.9 ppm, effects near 279 and 229 nm. The structure of 5 was conse- while C-3Ј, C-5Ј, and C-1Ј signals appeared downfield by quently determined to be (2R,3R)-2-(3Ј-hydroxybenzyl)-3- (3Љ-hydroxy-4Љ-methoxybenzyl)butyrolactone. Compound 6 was deduced to be a further demethylation Table 1. 13C-NMR (100 MHz) Spectral Data of Compounds 2—7 product of 5 on the basis of its molecular ion peak (m/z 314 ϩ a) a) a) a) b) a) C 2 3 4 5 6 7 [M] ) in the EI-MS spectrum, 14 mass units (CH2) less than that of 5, and no signal assignable to methoxy protons in the 1 178.7 179.5 178.9 178.7 181.4 179.0 1H-NMR spectrum. The 13C-NMR data agreed with those of 2 46.6 46.5 46.3 46.3 47.5 46.3 a synthetic lignan reported as an oxidative metabolite of en- 3 41.0 41.0 41.3 41.2 42.8 41.0 15) 4 71.3 71.6 71.4 71.3 72.8 71.4 terolactone by human liver microsomes. The CD spectrum 1Ј 129.5 130.6 139.5 139.5 140.9 139.4 of 6 also showed negative Cotton effects around 281 and 2Ј 111.6 116.1 116.2 116.2 117.3 116.3 230 nm. Therefore 6 was identified as (2R,3R)-2-(3Ј-hydroxy- 3Ј 146.7 143.9 156.1 155.9 158.6 155.91 benzyl)-3-(3Љ,4Љ-dihydroxybenzyl)butyrolactone. Ј 4 144.6 142.9 114.0 114.0 114.7 114.1 Compound 7 was detected as the final metabolite of arctiin 5Ј 114.1 115.2 129.8 130.0 130.6 130.0 6Ј 122.1 121.6 121.6 121.7 121.7 121.8 (1) by anaerobic incubation with a human fecal suspension. 7Ј 34.5 34.1 34.8 34.8 35.8 34.8 It showed a bright red spot on the TLC plates after spraying 1Љ 130.5 130.1 130.5 131.2 131.4 139.8 1 with anisaldehyde/H2SO4 followed by heating. The H- and 2Љ 111.9 112.0 112.0 114.8 116.8 115.7 13C-NMR spectra of 7 agreed well with those reported for 3Љ 149.1 149.1 149.1 145.6 146.4 155.87 16) 4Љ 147.9 147.9 147.9 145.4 145.0 113.9 enterolactone.
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