Dekant W
Department of Toxicology, University of Würzburg, FRG.
Arch Toxicol Suppl. 1996;18:163-72. doi: 10.1007/978-3-642-61105-6_17.
Nephrotoxicity is often observed as an endpoint in animal toxicity studies. In recent years, the mechanisms of biotransformation, which often provide the basis for renal toxicity, have been elucidated for a variety of compounds. These studies showed that nephrotoxicity of chemicals is either due to accumulation of certain metabolites in the kidney and further bioactivation or due to intrarenal bioactivation of the parent xenobiotic. Both types of mechanisms will be discussed using two relevant samples. The polychlorinated olefin hexachlorobutadiene and other haloolefins cause necrosis of the S-3 segment of the proximal tubules; their nephrotoxicity is dependent on bioactivation reactions. In the liver, hexachlorobutadiene is transformed by conjugation with glutathione to (S-pentachlorobutadienyl)glutathione. This S-conjugate is processed by the enzymes of mercapturic acid formation to give N-acetyl-(S-pentachlorobutadienyl)-L-cysteine, which is accumulated in the proximal tubule cells and deacetylated there to give (S-pentachlorobutadienyl)-L-cysteine. Further bioactivation is catalyzed by renal cysteine conjugate beta-lyase. Both the renal accumulation by the organic anion transporter and the topographical distribution of cysteine conjugate beta-lyase along the nephron are major determinants of organ and cell selectivity. Vinylidene chloride (VDC) is nephrotoxic in mice after inhalation, but not after oral or intraperitoneal administration. The nephrotoxicity of VDC is due to the selective expression of an androgen-dependent cytochrome P450 in the proximal tubules of male mice. This enzyme oxidizes VDC to an electrophile and is not present in female mice, but can be induced be androgen treatment. The observation of nephrotoxicity of VDC after inhalation only is due to the high blood flow to the kidney and thus high concentrations of VDC delivered to the kidney after inhalation. After oral or intraperitoneal application, hepatic first-pass metabolism efficiently reduces the amount of VDC delivered to the kidney. The results demonstrated here demonstrate that prior to in vitro nephrotoxicity screening, toxicokinetics and biotransformation pathways for a chemical have to be elucidated and metabolites have to be included into the testing regimen.
肾毒性在动物毒性研究中常被视作一个终点指标。近年来，生物转化机制（其常为肾毒性的基础）已针对多种化合物得以阐明。这些研究表明，化学物质的肾毒性要么归因于某些代谢物在肾脏中的蓄积及进一步的生物活化，要么归因于亲代异生物质在肾内的生物活化。将使用两个相关实例对这两种机制进行讨论。多氯烯烃六氯丁二烯及其他卤代烯烃会导致近端小管S-3段坏死；它们的肾毒性取决于生物活化反应。在肝脏中，六氯丁二烯通过与谷胱甘肽结合转化为（S-五氯丁二烯基）谷胱甘肽。这种S-结合物经巯基尿酸形成酶处理生成N-乙酰-（S-五氯丁二烯基）-L-半胱氨酸，其在近端小管细胞中蓄积并在那里脱乙酰基生成（S-五氯丁二烯基）-L-半胱氨酸。进一步的生物活化由肾半胱氨酸结合β-裂解酶催化。有机阴离子转运体介导的肾脏蓄积以及半胱氨酸结合β-裂解酶沿肾单位的拓扑分布均是器官和细胞选择性的主要决定因素。偏二氯乙烯（VDC）经吸入对小鼠具有肾毒性，但经口服或腹腔注射则无此毒性。VDC的肾毒性归因于雄性小鼠近端小管中雄激素依赖性细胞色素P450的选择性表达。该酶将VDC氧化为亲电试剂，雌性小鼠中不存在此酶，但可通过雄激素处理诱导产生。仅在吸入后观察到VDC的肾毒性是由于肾脏血流丰富，因此吸入后输送至肾脏的VDC浓度较高。经口服或腹腔给药后，肝脏首过代谢有效地减少了输送至肾脏的VDC量。此处展示的结果表明，在进行体外肾毒性筛查之前，必须阐明一种化学物质的毒代动力学和生物转化途径，并且必须将代谢物纳入测试方案中。
