Speerschneider P, Dekant W
Institut für Toxikologie, Universität Würzburg, FRG.
Toxicol Appl Pharmacol. 1995 Jan;130(1):48-56. doi: 10.1006/taap.1995.1007.
1,1-Dichloroethene is used as intermediate in the manufacture of polymers. In male mice, 1,1-dichloroethene caused renal tumors after inhalation. Renal tumors were not observed in female mice or in both sexes of rats. We investigated the metabolic basis for the species- and sex-specific nephrotoxicity and tumorigenicity of 1,1-dichloroethene. Kidney microsomes from male mice biotransformed 1,1-dichloroethene to chloroacetic acid; the amounts of chloroacetic acid formed were dependent on the hormonal status of the animals and correlated well with the ability of kidney microsomes to oxidize p-nitrophenol and chlorozoxazone, specific substrates for cytochrome P450 2E1. In kidney microsomes from naive females, significantly lower rates of oxidation of 1,1-dichloroethene, p-nitrophenol, and chlorozoxazone were observed; oxidation could be induced by testosterone. With a rabbit anti-rat liver cytochrome P450 2E1 antibody, a cross-reactive protein was detected in male mouse kidney microsomes with a molecular weight very similar to that of rat liver cytochrome P450 2E1; the expression of this protein was regulated by testosterone and correlated well with the ability of the microsomes to oxidize p-nitrophenol, chlorozoxazone, and 1,1-dichloroethene. When the relative cytochrome P450 2E1 contents of renal microsomes of male mice from different strains were compared, differences in the expression of cytochrome P450 2E1 were observed. Moreover, nephrotoxicity in Swiss-Webster mice after inhalation of 1,1-dichloroethene was observed only in males and testosterone-treated females, but not in naive females. In kidney microsomes obtained from both sexes of rats and in six samples of human kidney (male donors), no p-nitrophenol oxidase activity was detected. These data suggest that cytochrome P450 2E1 or a P450 enzyme with very similar molecular weight, substrate specificities, and immunological properties is expressed only in male mouse kidney and bioactivates 1,1-dichloroethene.
1,1 - 二氯乙烯用作聚合物生产的中间体。在雄性小鼠中，吸入1,1 - 二氯乙烯会导致肾肿瘤。在雌性小鼠或大鼠的雌雄两性中均未观察到肾肿瘤。我们研究了1,1 - 二氯乙烯物种和性别特异性肾毒性及致癌性的代谢基础。雄性小鼠的肾微粒体将1,1 - 二氯乙烯生物转化为氯乙酸；形成的氯乙酸量取决于动物的激素状态，并且与肾微粒体氧化对硝基苯酚和氯唑沙宗（细胞色素P450 2E1的特异性底物）的能力密切相关。在未接触过的雌性小鼠的肾微粒体中，观察到1,1 - 二氯乙烯、对硝基苯酚和氯唑沙宗的氧化速率显著较低；睾酮可诱导氧化。用兔抗大鼠肝细胞色素P450 2E1抗体在雄性小鼠肾微粒体中检测到一种交叉反应蛋白，其分子量与大鼠肝细胞色素P450 2E1非常相似；该蛋白的表达受睾酮调节，并且与微粒体氧化对硝基苯酚、氯唑沙宗和1,1 - 二氯乙烯的能力密切相关。当比较不同品系雄性小鼠肾微粒体中细胞色素P450 2E1的相对含量时，观察到细胞色素P450 2E1表达的差异。此外，吸入1,1 - 二氯乙烯后，仅在雄性和经睾酮处理的雌性瑞士 - 韦伯斯特小鼠中观察到肾毒性，而在未接触过的雌性小鼠中未观察到。在大鼠雌雄两性的肾微粒体以及六个男性供体的人肾样本中，均未检测到对硝基苯酚氧化酶活性。这些数据表明，细胞色素P450 2E1或分子量、底物特异性和免疫特性非常相似的P450酶仅在雄性小鼠肾中表达，并使1,1 - 二氯乙烯生物活化。
