Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University , 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan.
Chem Res Toxicol. 2011 Aug 15;24(8):1327-37. doi: 10.1021/tx200218u. Epub 2011 Jul 20.
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 3.6-5.7 μM; the values were lower than those with seen with P450 1A1 (19-30 μM) or 1A2 (6.3-13 μM). The K(s) values for Type I binding of P450 2A13 with m-XSC and BSC were both 0.20 μM; the values were very low compared to those for the interaction of P450 2A6 with m-XSC (5.7 μM) and BSC (2.0 μM). Four selenium compounds directly inhibited 7-ethoxyresorufin O-deethylation activities catalyzed by P450 1A1, 1A2, and 1B1 with IC(50) values <1.0 μM, except for the inhibition of P450 1A2 by BSC (1.3 μM). Coumarin 7-hydroxylation activities of P450 2A13 were more inhibited by four selenium compounds than those of P450 2A6, with IC(50) values of 0.22-1.4 μM for P450 2A13 and 2.4-6.2 μM 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.
几种有机硒化合物，包括苄基硒氰酸盐（BSC）、1,2-亚苯基双（亚甲基）硒氰酸盐（o-XSC）、1,3-亚苯基双（亚甲基）硒氰酸盐（m-XSC）和 1,4-亚苯基双（亚甲基）硒氰酸盐（p-XSC），已被证明可预防多环芳烃（PAHs）和 4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮（NNK）在实验动物中引起的癌症；这些化学致癌物质分别被人类 P450 1 和 2A 家族酶激活为致癌代谢物。在这项研究中，我们检查了这些硒化合物是否在体外与人类 P450 1 和 2A 酶相互作用并抑制其活性。四种有机硒化合物与 P450 1A1、1A2 和 1B1 产生反向 I 型结合光谱，并与 P450 2A6 和 2A13 产生 I 型结合光谱。与 P450 1B1 相互作用的这些化学物质的光谱解离常数（K(s)）为 3.6-5.7 μM；这些值低于与 P450 1A1（19-30 μM）或 1A2（6.3-13 μM）相互作用的 K(s)值。m-XSC 和 BSC 与 P450 2A13 的 I 型结合的 K(s)值均为 0.20 μM；与 P450 2A6 与 m-XSC（5.7 μM）和 BSC（2.0 μM）相互作用相比，这些值非常低。四种硒化合物直接抑制 P450 1A1、1A2 和 1B1 催化的 7-乙氧基荧光素 O-去乙基化活性，IC(50)值<1.0 μM，除 BSC 抑制 P450 1A2（1.3 μM）外。四种硒化合物对 P450 2A13 的香豆素 7-羟化活性的抑制作用强于 P450 2A6，P450 2A13 的 IC(50)值为 0.22-1.4 μM，而 P450 2A6 的 IC(50)值为 2.4-6.2 μM。四种有机硒化合物与人类 P450 酶相互作用的分子对接研究表明，这些化合物可以与这些人类 P450 酶的活性位点结合，并且这些化合物的硒氰酸盐官能团在 P450 1 和 2A 家族酶之间的位置不同。
