Metabolism of biochanin A and formononetin by human liver microsomes in vitro.
Biochanin A and formononetin are abundant in legumes. These proestrogenic isoflavones can be converted by 4'-O-demethylation to the more potent phytoestrogens genistein and daidzein. Incubation of biochanin A or formononetin with human liver microsomes resulted in 4'-O-demethylation and the production of additional metabolites. Three new hydroxylated formononetin derivatives, 6,7-dihydroxy-4'-methoxyisoflavone, 7,8-dihydroxy-4'-methoxyisoflavone, and 7,3'-dihydroxy-4'-methoxyisoflavone, were isolated and characterized. We surveyed the O-demethylase competence of cytochrome P450 isoforms found in human liver. Human cytochrome P450 isoforms 1A2, 2E1, 2C9*1, 2C19, and 2D6*1 catalyzed biochanin A consumption and genistein production. Human cytochrome P450 isoforms 1A2, 2C9*1, 2A6, 2D6*1, and 2C19 catalyzed formononetin consumption and daidzein production. These isoforms also generated other hydroxylated metabolites. Although O-demethylation of isoflavones has been attributed to metabolism by gut microflora, our study demonstrates that human hepatic microsomal enzymes can perform the same transformation and may play a key role in the conversion of 4'-O-methylated isoflavones to more potent phytoestrogens.
Tolleson
William H
WH
Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.
Doerge
Daniel R
DR
Churchwell
Mona I
MI
Marques
M Matilde
MM
Roberts
Dean W
DW
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019833:Genistein / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D007529:Isoflavones / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D051381:Rats
D007527:Isoenzymes; D007529:Isoflavones; C007768:formononetin; D009249:NADP; C004742:daidzein; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; C004541:biochanin A