Hanioka N, Omae E, Nishimura T, Jinno H, Onodera S, Yoda R, Ando M
Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan.
Chemosphere. 1996 Jul;33(2):265-76. doi: 10.1016/0045-6535(96)00169-5.
We studied the effects of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) on the kinetics of the cytochrome P450 (P450)-dependent monooxygenases in rat liver microsomes. The activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) in rat liver microsomes exposed to 3-methylcholanthrene (MC) and phenobarbital (PB) respectively, were substantially inhibited by Irgasan DP300. The inhibition profile of EROD was competitive, whereas that of PROD was noncompetitive; the Ki values from Hanes plots were 0.24 and 1.48 microM for EROD and PROD, respectively. Phenacetin O-deethylase (PCOD) and 4-nitrophenol hydroxylase (4NPH) activities in rats exposed to PB were also inhibited by Irgasan DP300, at Ki values lower than those for other microsomes. Irgasan DP300 slightly inhibited testosterone 6 beta-hydroxylase (TS6BH) activities in some microsomes. No effect of Irgasan DP300 on lauric acid omega-hydroxylase (LAOH) activity was evident in any microsomal preparations. These results indicated that Irgasan DP300 inhibits MC- and PB-inducible P450-dependent monoxygenase in vitro competitively or noncompetitively, and that the P450 enzymes of the CYP1A or CYP2B subfamily may contribute to Irgasan DP300 toxicity.
我们研究了2,4,4'-三氯-2'-羟基二苯醚（三氯生）对大鼠肝微粒体中细胞色素P450（P450）依赖性单加氧酶动力学的影响。分别暴露于3-甲基胆蒽（MC）和苯巴比妥（PB）的大鼠肝微粒体中，7-乙氧基异吩恶唑酮O-脱乙基酶（EROD）和7-戊氧基异吩恶唑酮O-脱戊基酶（PROD）的活性被三氯生显著抑制。EROD的抑制模式为竞争性，而PROD的抑制模式为非竞争性；根据Hanes图计算，EROD和PROD的Ki值分别为0.24和1.48 microM。暴露于PB的大鼠中，非那西丁O-脱乙基酶（PCOD）和4-硝基苯酚羟化酶（4NPH）的活性也被三氯生抑制，其Ki值低于其他微粒体。三氯生在某些微粒体中轻微抑制睾酮6β-羟化酶（TS6BH）的活性。在任何微粒体制剂中，均未发现三氯生对月桂酸ω-羟化酶（LAOH）活性有明显影响。这些结果表明，三氯生在体外竞争性或非竞争性地抑制MC和PB诱导的P450依赖性单加氧酶，并且CYP1A或CYP2B亚家族的P450酶可能与三氯生的毒性有关。
