Transformation of arctiin to estrogenic and antiestrogenic substances by human intestinal bacteria.
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.
Xie
Li-Hua
LH
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Japan.
Ahn
Eun-Mi
EM
Akao
Teruaki
T
Abdel-Hafez
Atef Abdel-Monem
AA
Nakamura
Norio
N
Hattori
Masao
M
D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D001711:Biotransformation; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005243:Feces / Q000382:microbiology; D005663:Furans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005960:Glucosides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology*; D008297:Male; D010462:Peptostreptococcus / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020847:Estrogen Receptor Modulators; D004967:Estrogens; D005663:Furans; D005960:Glucosides; C077992:arctiin