Transformation of Arctiin to Estrogenic and Antiestrogenic Substances by Human Intestinal Bacteria.

Abstract

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'-dihydroxybenzyl)-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 spectroscopic 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. Enterolactones 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 microM. 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.

Biotransformation of Pinoresinol Diglucoside to Mammalian Lignans by Human Intestinal Microflora, and Isolation of Enterococcus faecalis Strain PDG-1 Responsible for the Transformation of (+)-Pinoresinol to (+)-Lariciresinol

“…The methoxy group was assigned at C-3 on the basis of the HMBC experiment; the following correlations were observed between signals of methoxy protons and C-3Ј; H-5Ј and C-3Ј or C-1Ј; H-7Ј and C-1Ј, C-6Ј, C-1 or C-2. Similar to those of 2R,3R-dibenzylbutyrolactones, 11,21) compound 11 showed a minus optical rotation, indicating a (2R,3R) configuration. The structure of 11 was consequently determined to be (Ϫ)-(2R,3R)-3-(3Љ,4Љ-dihydroxybenzyl)-2-(4Ј-hydroxy-3Ј-methoxybenzyl)butyrolactone.…”

“…Of these plant lignans, secoisolariciresinol diglucoside (SDG) and arctiin (the glucoside of arctigenin) are the only two, of which the transformation pathways by human intestinal microflora were extensively studied. 9,11) The transformation of SDG by human intestinal microflora includes four types of reactions, hydrolysis of glucoside, demethylation of a methoxy group, elimination of a 4-hydroxy group in the 3,4-dihydroxyphenyl moiety, and oxidation of dibenzylbutanediol to dibenzylbutyrolactone. 9) Meanwhile, the transformation of arctiin, already bearing a butyrolactone structure, consists of the first three types of reactions as mentioned above for SDG.…”

“…First, hydrolysis of lignan glucosides to their aglycones is the first step of transformation, and it is generally finished within 12 h (under the conditions used in our experiments). 9,11) Second, demethylation of a methoxy group adjacent to a hydroxy group easily takes place, compared with that of two vicinal methoxy groups.…”

“…9,11) Fourth, the oxidation of dibenzylbutanediols to dibenzylbutyrolactone may occur at each step, such as 6 to 11, 7 to 12, 8 to 13, 9 to 14 or 15, and 10 to 16, in which the oxidation seems to proceed with no change in the absolute configuration […”

“…[7][8][9] Pinoresinol, lariciresinol, syringaresinol, 7-hydoxymatairesinol and arctigenin are newly identified enterolactone precursors, 10,11) and a possible metabolic pathway for pinoresinol (formation of mammalian lignans via lariciresinol and secoisolariciresinol) was proposed based on the biosynthetic pathway of secoisolariciresinol and matairesinol in plants. 10) Pinoresinol diglucoside is a major antihypertensive principle of Tu-Chung (the bark of Eucommia ulmoides), used in traditional Chinese medicine, 12) and pinoresinol is contained in cereals, particularly in whole-grain rye products, 1) olive oil, 13) and in various Picea, Pinus and Abies etc.…”