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Vol. 299, Issue 3, 874-882, December 2001

Differential Inhibition and Inactivation of Human CYP1 Enzymes by trans-Resveratrol: Evidence for Mechanism-Based Inactivation of CYP1A2

Thomas K. H. Chang, Jie Chen and Wendy B. K. Lee

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

trans-Resveratrol (3,5,4'-trihydroxy-trans-stilbene) has been reported to confer chemoprotection against 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenicity in a murine model. A potential mechanism for this effect by trans-resveratrol is inhibition of DMBA-bioactivating cytochrome P450 (CYP) enzymes such as CYP1B1, CYP1A1, and CYP1A2. In the present study, we examined in detail the in vitro inhibitory effects of trans-resveratrol on these three human CYP enzymes. trans-Resveratrol decreased 7-ethoxyresorufin O-dealkylation activity catalyzed by human recombinant CYP1B1, CYP1A1, and CYP1A2 in a concentration-dependent manner and by a mixed type of inhibition. This direct inhibition was enzyme-selective, as judged by the differences in the apparent Ki values (0.8 ± 0.1 µM, 1.2 ± 0.1 µM, and 15.5 ± 1.1 µM for CYP1B1, CYP1A1, and CYP1A2, respectively). Preincubating recombinant CYP1A2 or human liver microsomes with trans-resveratrol and NADPH prior to the initiation of substrate oxidation resulted in a time- and concentration-dependent decrease in catalytic activity. The inactivation of liver microsomal CYP1A2 by trans-resveratrol required NADPH, was not reversible by dialysis, and was not affected by the trapping agents glutathione, N-acetylcysteine, catalase, or superoxide dismutase, but was attenuated by a CYP1A2 substrate, imipramine. Analysis of a panel of individual human liver microsomes showed intersample differences in the response to the in vitro inactivation by trans-resveratrol. In contrast to CYP1A2, CYP1B1 was not subject to inactivation by this compound and the reduction in CYP1A1 activity was time- but not concentration-dependent. In summary, trans-resveratrol differentially inhibited human CYP1 enzymes and this occurred by two distinct mechanisms: direct inhibition (mainly CYP1B1 and CYP1A1) and mechanism-based inactivation (CYP1A2).

0022-3565/01/2993-0874$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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