title: In vitro assessment of inhibition by natural polyphenols of metabolic activation of procarcinogens by human CYP1A1.
abstract: Previously, inhibitors of CYP1A1 were rated as candidate chemopreventive agents against cancer mainly according to their effects on the 7-ethoxyresorufin O-deethylation (EROD) of diagnostic probe substrates. Surprisingly, several polyphenols including resveratrol, formerly identified as potent inhibitors by the EROD assay, exhibited no or weak inhibition of procarcinogen activation. We compared the effects of 11 representative natural polyphenols, which normally occur in food, on different activities of CYP1A1, namely epoxidation of 7,8-dihydrodiol-benzo[a]pyrene, the terminal step in the activation leading to the ultimate carcinogenic diolepoxides, hydroxylation of benzo[a]pyrene, and EROD. For the first time, a reconstituted system was used for the determination of IC(50) values, consisting of purified enzymes (human CYP1A1 and human NADPH-cytochrome P450 reductase) and dilaurylphosphatidylcholine. The results demonstrate that the inhibitory effects of dietary polyphenols on CYP1A1 activity depend on both the structure of the inhibitor and the type of the reaction and substrate used in the assay. Consequently, a potent EROD inhibition alone is insufficient to count a substance among the chemoprotective agents.
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, Schumannstr. 20/21, 10098 Berlin, Germany. dieter.schwarz@charite.de
authors.forename: Dieter
authors.initials: D
authors.lastname: Schwarz
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens / Q000493:pharmacokinetics*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids; D006801:Humans; D066298:In Vitro Techniques; D010636:Phenols / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D013267:Stilbenes; D001564:Benzo(a)pyrene; D002392:Catechin; C045651:epigallocatechin gallate; D019363:Cytochrome P-450 CYP1A1; D000077185:Resveratrol