Njoku D B, Pohl L R, Sokoloski E A, Marchick M R, Borkowf C B, Martin J L
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Anesthesiology. 1999 Feb;90(2):458-69. doi: 10.1097/00000542-199902000-00021.
Compound A, a degradation product of sevoflurane, causes renal corticomedullary necrosis in rats. Although the toxicity of this compound was originally hypothesized to result from the biotransformation of its cysteine conjugates into toxic thionoacyl halide metabolites by renal cysteine conjugate beta-lyase, recent evidence suggests that alternative mechanisms may be responsible for compound A nephrotoxicity. The aim of this study was to evaluate these issues by determining whether mercapturates and glutathione conjugates of compound A could produce renal corticomedullary necrosis in rats, similar to compound A, and whether renal covalent adducts of the thionacyl halide metabolite of compound A could be detected immunochemically.
Male Wistar rats were administered, intraperitoneally, N-acetylcysteine conjugates (mercapturates) of compound A (90 or 180 micromol/kg) or glutathione conjugates of compound A (180 micromol/kg) with or without intraperitoneal pretreatments with aminooxyacetic acid (500 micromol/kg) or acivicin (250 micromol/kg). Rats were killed after 24 h, and kidney tissues were analyzed for toxicity by histologic examination or for protein adducts by immunoblotting or immunohistochemical analysis, using antisera raised against the covalently bound thionoacyl halide metabolite of compound A.
Mercapturates and glutathione conjugates of compound A both produced renal corticomedullary necrosis similar to that caused by compound A. Aminooxyacetic acid, an inhibitor of renal cysteine conjugate beta-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibitor of gamma-glutamyltranspeptidase, potentiated the toxicity of both classes of conjugates. No immunochemical evidence for renal protein adducts of the thionacyl halide metabolite was found in rats 24 h after the administration of the mercapturates of compound A or in the kidneys of rats, obtained from a previous study, 5 and 24 h after the administration of compound A.
The results of this study are consistent with the idea that a mechanism other than the renal cysteine conjugate beta-lyase pathway of metabolic activation is responsible for the nephrotoxicity of compound A and its glutathione and mercapturate conjugates in male Wistar rats.
化合物A是七氟醚的一种降解产物，可导致大鼠肾皮质髓质坏死。尽管最初推测该化合物的毒性是由于其半胱氨酸共轭物经肾半胱氨酸共轭物β-裂解酶生物转化为有毒的硫代酰卤代谢产物所致，但最近的证据表明，其他机制可能与化合物A的肾毒性有关。本研究的目的是通过确定化合物A的硫醇尿酸盐和谷胱甘肽共轭物是否能像化合物A一样在大鼠中产生肾皮质髓质坏死，以及是否能通过免疫化学方法检测到化合物A的硫代酰卤代谢产物的肾共价加合物，来评估这些问题。
雄性Wistar大鼠腹腔注射化合物A的N-乙酰半胱氨酸共轭物（硫醇尿酸盐）（90或180 μmol/kg）或化合物A的谷胱甘肽共轭物（180 μmol/kg），同时或不同时腹腔预处理氨基氧乙酸（500 μmol/kg）或阿西维辛（250 μmol/kg）。24小时后处死大鼠，通过组织学检查分析肾组织的毒性，或通过免疫印迹或免疫组织化学分析，使用针对化合物A共价结合的硫代酰卤代谢产物产生的抗血清分析蛋白质加合物。
化合物A的硫醇尿酸盐和谷胱甘肽共轭物均产生了与化合物A所致相似的肾皮质髓质坏死。肾半胱氨酸共轭物β-裂解酶抑制剂氨基氧乙酸并未抑制硫醇尿酸盐的毒性，而γ-谷氨酰转肽酶抑制剂阿西维辛则增强了这两类共轭物的毒性。在给予化合物A的硫醇尿酸盐24小时后的大鼠中，或在先前研究中给予化合物A 5小时和24小时后的大鼠肾脏中，均未发现硫代酰卤代谢产物的肾蛋白加合物免疫化学证据。
本研究结果与以下观点一致，即除肾半胱氨酸共轭物β-裂解酶代谢活化途径外的其他机制，是雄性Wistar大鼠中化合物A及其谷胱甘肽和硫醇尿酸盐共轭物肾毒性的原因。
