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