title: Effect of trans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarin O-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5.
abstract: Red wine concentrate has been reported to inhibit the catalytic activity of human recombinant cytochrome P450 (CYP) 3A4. Wine contains many polyphenolic compounds, including trans-resveratrol, which is also available commercially as a nutraceutical product. In the present study, we examined the in vitro effect of trans-resveratrol on human CYP3A catalytic activity by employing recombinant CYP3A4 and CYP3A5 as model enzymes and 7-benzyloxy-4-trifluoromethylcoumarin (BFC) as a CYP3A substrate. Trans-resveratrol inhibited BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 in a concentration-dependent manner. In each case, the inhibition was noncompetitive, as determined by Lineweaver-Burk and Dixon plots of the enzyme kinetic data. The apparent Ki values (mean +/- SEM) for the inhibition by trans-resveratrol of BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 were 10.2+/-1.1 microM and 14.7+/-0.3 microM, respectively. Preincubation of trans-resveratrol with NADPH and CYP3A4 or CYP3A5 for 10 or 15 min prior to initiation of substrate oxidation did not enhance the inhibitory effect, suggesting that this compound was not a mechanism-based inactivator of CYP3A4 or CYP3A5 when BFC was used as the substrate. Overall, our study provides the first demonstration that trans-resveratrol inhibits, in vitro, a substrate oxidation reaction catalyzed by human recombinant CYP3A4 and CYP3A5.
authors: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada. tchang@unixg.ubc.ca
authors: T K
authors: TK
authors: Chang
authors: R K
authors: RK
authors: Yeung
mesh_terms: D002384:Catalysis; D003374:Coumarins / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C419147:7-benzyloxy-4-trifluoromethylcoumarin; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011994:Recombinant Proteins; D013267:Stilbenes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077185:Resveratrol