Inhibition of mouse and human CYP 1A- and 2E1-dependent substrate metabolism by the isoflavonoids genistein and equol.
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.
Helsby
N A
NA
School of Biochemistry, University of Birmingham, Edgbaston, UK.
Chipman
J K
JK
Gescher
A
A
Kerr
D
D
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
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