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Cytochrome P4501B1: a target for inhibition in anticarcinogenesis strategies

Authors
Guengerich, F.P.Chun, Y.-J.Kim, D.Gillam, E.M.J.Shimada, T.
Issue Date
Feb-2003
Publisher
ELSEVIER SCIENCE BV
Keywords
cytochrome P4501B1; inhibition of cytochrome P450; estrogen hydroxylation; inhibition of heterocyclic amines; inhibition of activation; anticarcinogenesis; strategies; inhibition of activation of benzo[a]pyrene
Citation
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, v.523, pp 173 - 182
Pages
10
Journal Title
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume
523
Start Page
173
End Page
182
URI
https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/53137
DOI
10.1016/S0027-5107(02)00333-0
ISSN
0027-5107
1873-135X
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 3 nM, 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. (C) 2002 Elsevier Science B.V. All rights reserved.
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