Spectral Modification and Catalytic Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2A6, and 2A13 by Four Chemopreventive Organoselenium Compounds

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• 作者：Tsutomu Shimada ; Norie Murayama ; Katsuhiro Tanaka ; Shigeo Takenaka ; F. Peter Guengerich ; Hiroshi Yamazaki ; Masayuki Komori
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：August 15, 2011
• 年：2011
• 卷：24
• 期：8
• 页码：1327-1337
• 全文大小：1125K
• 年卷期：v.24,no.8(August 15, 2011)
• ISSN：1520-5010

文摘

Several organoselenium compounds including benzyl selenocyanate (BSC), 1,2-phenylenebis(methylene)selenocyanate (o-XSC), 1,3-phenylenebis(methylene)selenocyanate (m-XSC), and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) have been shown to prevent cancers caused by polycyclic aromatic hydrocarbons (PAHs) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in experimental animals; these chemical carcinogens are activated by human P450 1 and 2A family enzymes, respectively, to carcinogenic metabolites. In this study, we examined whether these selenium compounds interact with and inhibit human P450 1 and 2A enzymes in vitro. Four organoselenium compounds induced reverse Type I binding spectra with P450 1A1, 1A2, and 1B1 and Type I binding spectra with P450 2A6 and 2A13. The spectral dissociation constants (K_s) for the interaction of P450 1B1 with these chemicals were 3.6鈥?.7 渭M; the values were lower than those with seen with P450 1A1 (19鈥?0 渭M) or 1A2 (6.3鈥?3 渭M). The K_s values for Type I binding of P450 2A13 with m-XSC and BSC were both 0.20 渭M; the values were very low compared to those for the interaction of P450 2A6 with m-XSC (5.7 渭M) and BSC (2.0 渭M). Four selenium compounds directly inhibited 7-ethoxyresorufin O-deethylation activities catalyzed by P450 1A1, 1A2, and 1B1 with IC₅₀ values <1.0 渭M, except for the inhibition of P450 1A2 by BSC (1.3 渭M). Coumarin 7-hydroxylation activities of P450 2A13 were more inhibited by four selenium compounds than those of P450 2A6, with IC₅₀ values of 0.22鈥?.4 渭M for P450 2A13 and 2.4鈥?.2 渭M for P450 2A6. Molecular docking studies of the interaction of four organoselenium compounds with human P450 enzymes suggest that these chemicals can be docked into the active sites of these human P450 enzymes and that the sites of the selenocyanate functional groups of these chemicals differ between the P450 1 and 2A family enzymes.