Lash L H, Parker J C
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201-1928, USA.
Pharmacol Rev. 2001 Jun;53(2):177-208.
Metabolism of perchloroethylene (Perc) occurs by cytochrome P450-dependent oxidation and glutathione (GSH) conjugation. The cytochrome P450 pathway generates tri- and dichloroacetate as metabolites of Perc, and these are associated with hepatic toxicity and carcinogenicity. The GSH conjugation pathway is associated with generation of reactive metabolites selectively in the kidneys and with Perc-induced renal toxicity and carcinogenicity. Physiologically based pharmacokinetic models have been developed for Perc in rodents and in humans. We propose the addition of a submodel that incorporates the GSH conjugation pathway and the kidneys as a target organ. Long-term bioassays of Perc exposure in laboratory animals have identified liver tumors in male and female mice, kidney tumors in male rats, and mononuclear cell leukemia in male and female rats. Increases in incidence of non-Hodgkin's lymphoma and of cervical, esophageal, and urinary bladder cancer have been observed for workers exposed to Perc. Limited, and not always consistent, evidence is available concerning the kidneys as a target organ for Perc in humans. Three potential modes of action for Perc-induced liver tumorigenesis are: 1) modification of signaling pathways; 2) cytotoxicity, cell death, and reparative hyperplasia; and 3) direct DNA damage. Four potential modes of action for Perc-induced renal tumorigenesis are: 1) peroxisome proliferation, 2) alpha-2u-globulin nephropathy, 3) genotoxicity leading to somatic mutation, and 4) acute cytotoxicity and necrosis leading to cell proliferation. Finally, the epidemiological and experimental data are assessed and use of toxicity information in the development of a reference dose and a reference concentration for human Perc exposure are presented.
全氯乙烯（Perc）的代谢通过细胞色素P450依赖性氧化和谷胱甘肽（GSH）结合作用进行。细胞色素P450途径产生三氯乙酸和二氯乙酸作为Perc的代谢产物，这些产物与肝脏毒性和致癌性相关。GSH结合途径与肾脏中选择性地产生反应性代谢产物以及Perc诱导的肾脏毒性和致癌性有关。已经针对啮齿动物和人类开发了基于生理的全氯乙烯药代动力学模型。我们建议添加一个子模型，该模型纳入GSH结合途径并将肾脏作为靶器官。实验室动物长期暴露于Perc的生物测定已确定雄性和雌性小鼠有肝肿瘤，雄性大鼠有肾肿瘤，雄性和雌性大鼠有单核细胞白血病。已观察到接触Perc的工人中非霍奇金淋巴瘤以及宫颈癌、食管癌和膀胱癌的发病率增加。关于肾脏作为人类Perc靶器官的证据有限且并不总是一致。Perc诱导肝肿瘤发生的三种潜在作用模式是：1）信号通路的改变；2）细胞毒性、细胞死亡和修复性增生；3）直接DNA损伤。Perc诱导肾肿瘤发生的四种潜在作用模式是：1）过氧化物酶体增殖，2）α-2u球蛋白肾病，3）导致体细胞突变的遗传毒性，4）导致细胞增殖的急性细胞毒性和坏死。最后，对流行病学和实验数据进行了评估，并介绍了在制定人类Perc暴露的参考剂量和参考浓度时毒性信息的使用情况。
