Inhibition of Extrahepatic Human Cytochromes P450 1A1 and 1B1 by Metabolism of Isoflavones Found in Trifolium pratense (Red Clover)

Biochanin A and formononetin are the predominant isoflavones in red clover. In a previous study (J. Agric. Food Chem. 2002, 50, 4783−4790), it was demonstrated that human liver microsomes converted biochanin A and formononetin to genistein and daidzein. This paper now shows CYP1B1-catalyzed O-demeth...

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Published in:Journal of agricultural and food chemistry 2004-10, Vol.52 (21), p.6623-6632
Main Authors: Roberts, Dean W, Doerge, Daniel R, Churchwell, Mona I, Gamboa da Costa, Gonçalo, Marques, M. Matilde, Tolleson, William H
Format: Article
Language:English
Subjects:
Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors
biochanin A
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
cytochrome P-450
Cytochrome P-450 CYP1A1 - antagonists & inhibitors
Cytochrome P-450 CYP1B1
daidzein
enzyme inhibition
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Foods and miscellaneous
formononetin
genistein
Genistein - metabolism
Genistein - pharmacology
Humans
isoflavones
Isoflavones - metabolism
Isoflavones - pharmacology
liver microsomes
Medical sciences
medicinal properties
metabolism
plant estrogens
Trifolium - chemistry
Trifolium pratense
Tumors
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Summary:Biochanin A and formononetin are the predominant isoflavones in red clover. In a previous study (J. Agric. Food Chem. 2002, 50, 4783−4790), it was demonstrated that human liver microsomes converted biochanin A and formononetin to genistein and daidzein. This paper now shows CYP1B1-catalyzed O-demethylation of biochanin A and formononetin to produce genistein and daidzein, respectively, which inhibit CYP1B1. Recombinant human CYP1A1 or CYP1B1 was incubated with biochanin A or formononetin. CYP1A1 catalyzed isoflavone 4‘-O-demethylation and hydroxylations with similar efficiency, whereas CYP1B1 favored 4‘-O-demethylation over hydroxylations. Three of the biochanin A metabolites (5,7,3‘-trihydroxy-4‘-methoxyisoflavone, 5,7,8-trihydroxy-4‘-methoxyisoflavone, and 5,6,7-trihydroxy-4‘-methoxyisoflavone) were characterized by 1H NMR spectroscopy and mass spectrometry. Daidzein (K i = 3.7 μM) exhibited competitive inhibition of CYP1B1 7-ethoxyresorufin O-deethylase activity, and genistein (K i = 1.9 μM) exhibited mixed inhibition. Biochanin A and/or formononetin may exert anticarcinogenic effects directly by acting as competitive substrates for CYP1B1 or indirectly through their metabolites daidzein and genistein, which inhibit CYP1B1. Keywords: Biochanin A; CYP1A1; CYP1B1; cytochrome P450; demethylation; enzyme inhibition; extrahepatic metabolism; formononetin; hydroxylation; isoflavones; Trifolium pratense
ISSN:0021-8561
1520-5118
DOI:10.1021/jf049418x