title: Potent inhibition of human cytochrome P450 1 enzymes by dimethoxyphenylvinyl thiophene.
abstract: Cytochrome P450 (P450) 1 enzymes such as P450 1A1, 1A2, and 1B1 are known to be involved in the oxidative metabolism of various procarcinogens and are regarded as important target enzymes for cancer chemoprevention. Previously, several hydroxystilbene compounds were reported to inhibit P450 1 enzymes and were rated as candidate chemopreventive agents. In this study, we investigated the inhibitory effect of 2-[2-(3,5-dimethoxyphenyl)vinyl]-thiophene (DMPVT), produced from the chemical modification of oxyresveratrol, on the activities of P450 1 enzymes. The inhibitory potential by DMPVT on the P450 1 enzyme activity was evaluated with the Escherichia coli membranes of the recombinant human cytochrome P450 1A1, 1A2, or 1B1 coexpressed with human NADPH-P450 reductase. DMPVT significantly inhibited ethoxyresorufin O-deethylation (EROD) activities with IC50 values of 61, 11, and 2 nM for 1A1, 1A2, and 1B1, respectively. The EROD activity in DMBA-treated rat lung microsomes was also significantly inhibited by DMPVT in a dose-dependent manner. The modes of inhibition by DMPVT were non-competitive for all three P450 enzymes. The inhibition of P450 1B1-mediated EROD activity by DMPVT did not show the irreversible mechanism-based effect. The loss of EROD activity in P450 1B1 with DMPVT incubation was not blocked by treatment with the trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol. Taken together, the results suggested DMPVT to be a strong noncompetitive inhibitor of human P450 1 enzymes that should be considered as a good candidate for a cancer chemopreventive agent in humans.
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea.
authors.forename: Sang-Kwang
authors.initials: SK
authors.lastname: Lee
authors.forename: Yongmo
authors.initials: Y
authors.lastname: Kim
authors.forename: Mie Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Chun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D013876:Thiophenes; C490433:dimethoxyphenylvinyl thiophene; D009249:NADP; D019363:Cytochrome P-450 CYP1A1