title: Potent inhibition of human cytochrome P450 1B1 by tetramethoxystilbene.
abstract: Human cytochrome P450 1B1 (CYP1B1) is found mainly in extrahepatic tissues and is overexpressed in a variety of human tumors. Metabolic activation of 17beta-estradiol (E2) to 4-hydroxy E2 by CYP1B1 has been postulated to be an important factor in mammary carcinogenesis. The inhibition of recombinant human CYP1B1 by 2,2',4,6'-tetramethoxystilbene (TMS) was investigated using either the Escherichia coli membranes of recombinant human CYP1B1 coexpressed with human NADPH-P450 reductase or using purified enzyme. 2,2',4,6'-TMS showed potent and selective inhibition of ethoxyresorufin O-deethylation (EROD) activity of CYP1B1 with IC(50) values of 2 nM. 2,2',4,6'-TMS exhibited 175-fold selectivity for CYP1B1 over CYP1A1 (IC(50), 350 nM) and 85-fold selectivity for CYP1B1 over CYP1A2 (IC(50), 170 nM). However, inhibition of human NADPH-P450 reductase activity by 2,2',4,6'-TMS was negligible. The modes of inhibition by 2,2',4,6'-TMS were noncompetitive for CYP1A1 and CYP1B1. Moreover, 2,2',4,6'-TMS significantly suppressed EROD activity and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 or CYP1B1 gene expression in human tumor cells such as HepG2 and MCF-10A. Taken together, our results indicate that 2,2',4,6'-TMS is a potently selective inhibitor of human CYP1B1 as well as a suppressor of CYP1B1 expression and may be a valuable tool for determining enzyme properties of human CYP1B1.
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. yjchun@cau.ac.kr
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Chun
authors.forename: Young-Kun
authors.initials: YK
authors.lastname: Oh
authors.forename: Beom Joon
authors.initials: BJ
authors.lastname: Kim
authors.forename: Donghak
authors.initials: D
authors.lastname: Kim
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Kim
authors.forename: Hyung-Kyoon
authors.initials: HK
authors.lastname: Choi
authors.forename: Mie-Young
authors.initials: MY
authors.lastname: Kim
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C541980:2,2',4,6'-tetramethoxystilbene; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D011994:Recombinant Proteins; D013267:Stilbenes; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1