title: Cytochrome P450 1B1: a target for inhibition in anticarcinogenesis strategies.
abstract: Cytochrome P450 (P450) 1B1 is expressed in a number of human tissues in which cancers occur (e.g. prostate, ovary, uterus, mammary gland). P450 1B1 activates many environmental mutagens and also catalyzes the 4-hydroxylation of estrogens, considered to be an important step in hormonal carcinogenesis. We have examined the activities of several of the major allelic variants of human P450 1B1 in these reactions. Another interest has been the development of chemical inhibitors of P450 1B1. 2-Ethynylpyrene and alpha-naphthoflavone preferentially inhibit human P450 1B1 compared to P450 1A1, which may be present in the same tissue sites. The natural product resveratrol is also an inhibitor of P450 1B1. Further studies with rhapontigenin and synthetic stilbenes led to the discovery of 2,4,3',5'-tetramethoxystilbene, a selective inhibitor of P450 1B1 relative to other P450s. Inhibition is competitive, with a K(i) value of 3nM, and the inhibitor is resistant to metabolism. In addition to blocking 17beta-estradiol 4-hydroxylation, this stilbene also inhibited the activation of heterocyclic amines to mutagens. 2,4,3',5'-Tetramethoxystilbene also suppressed expression of P450 1B1 and growth of human mammary tumor cells. 3,3',4',5,5'-Pentamethoxystilbene was a selective inhibitor of P450 1A1, showing mixed inhibition, and also suppressed P450 1A1 expression in HepG2 cells. Substituted stilbenes may be useful in preventing cancer caused by estrogens and xenobiotics.
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23rd Pierce Avenue, Nashville, TN 37232-0146, USA. guengerich@toxicology.mc.vanderbilt.edu
authors.forename: F
authors.initials: F
authors.lastname: Peter Guengerich
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Chun
authors.forename: Donghak
authors.initials: D
authors.lastname: Kim
authors.forename: Elizabeth M J
authors.initials: EM
authors.lastname: Gillam
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
mesh_terms: D000483:Alleles; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005833:Genital Neoplasms, Female / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation
chemical_list: D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1