Hepatic and renal toxicities associated with perchloroethylene.
Hepatic and renal toxicities associated with perchloroethylene.
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DOI：
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发表时间：
2001-06
影响因子：
21.1
通讯作者：
L. Lash;J. C. Parker
中科院分区：
文献类型：
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作者：
L. Lash;J. C. Parker
过氯乙烯（Perc）的代谢是通过细胞色素p450依赖性氧化和谷胱甘肽（GSH）偶联发生的。细胞色素P450途径产生三氯乙酸和二氯乙酸作为Perc的代谢物，这些与肝毒性和致癌性有关。谷胱甘肽偶联途径与肾脏选择性产生反应性代谢物有关，并与perc诱导的肾毒性和致癌性有关。基于生理学的药代动力学模型已经在啮齿类动物和人类中开发出来。我们建议增加一个结合谷胱甘肽偶联途径和肾脏作为靶器官的子模型。实验动物暴露于Perc的长期生物测定已经在雄性和雌性小鼠中发现肝脏肿瘤，在雄性大鼠中发现肾脏肿瘤，在雄性和雌性大鼠中发现单核细胞白血病。在接触Perc的工人中，非霍奇金淋巴瘤和宫颈癌、食道癌和膀胱癌的发病率有所增加。关于肾脏作为人体Perc靶器官的证据有限，而且并不总是一致。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)直接的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 - u-球蛋白肾病，3)导致体细胞突变的遗传毒性，以及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，并介绍了在制定人体全氯暴露参考剂量和参考浓度时使用毒性信息的情况。
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.