title: Inhibition of mouse and human CYP 1A- and 2E1-dependent substrate metabolism by the isoflavonoids genistein and equol.
abstract: The inhibitory effect of the isoflavonoids genistein and equol on cytochrome P450 activities has been investigated. Genistein and equol inhibited the high capacity component of p-nitrophenol (CYP2E1 substrate) metabolism in liver microsomes from acetone-induced mice with IC50 values of approximately 10 mM and 560 microM, respectively (cf. diethyldithiocarbamate, IC50, 69 microM). Using human CYP2E1 from a specific expression system (which overcame multienzyme involvement in the rodent system), non-competitive inhibition was also seen with both isoflavonoids. Genistein and equol also inhibited the high capacity component of ethoxyresorufin (CYP1A substrate) metabolism in liver microsomes from beta-naphthoflavone-induced mice with IC50 values of 5.6 mM and 1.7 mM, respectively (cf. alpha-naphthoflavone, IC50 0.8 microM). Using human CYPIA2 from a specific expression system, noncompetitive inhibition was seen with both isoflavonoids. CYP1A1 inhibition offers a possible explanation for the chemopreventative effect of genistein against, for example, dimethylbenz[a]anthracene genotoxicity reported in animals but the IC50 values negate the relevance of this specific chemopreventative action at the levels likely to be achieved from the human diet.
authors.affiliation: School of Biochemistry, University of Birmingham, Edgbaston, UK.
authors.forename: N A
authors.initials: NA
authors.lastname: Helsby
authors.forename: J K
authors.initials: JK
authors.lastname: Chipman
authors.forename: A
authors.initials: A
authors.lastname: Gescher
authors.forename: D
authors.initials: D
authors.lastname: Kerr
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed / Q000201:enzymology; D002839:Chromans / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D060754:Equol; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009596:Nitrophenols / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
chemical_list: C007610:4',7-dihydroxy-3,4-dihydroisoflavone; D002839:Chromans; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D007529:Isoflavones; D008996:Monoamine Oxidase Inhibitors; D009596:Nitrophenols; D010078:Oxazines; D060754:Equol; C007649:ethoxyresorufin; D019833:Genistein; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; C024836:4-nitrophenol