Immunochemical evidence against the involvement of cysteine conjugate beta-lyase in compound A nephrotoxicity in rats

Background: Compound A, a degradation product of sevoflurane, causes renal corticomedullary necrosis in rats. Although the toxicity of this compound w as originally hypothesized to result from the biotransformation of its cyst eine 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 glutathi one conjugates of compound A could produce renal corticomedullary necrosis in rats, similar to compound A, and whether renal covalent adducts of the t hionacyl halide metabolite of compound A could be detected immunochemically . Methods: Male Wistar rats were administered, intraperitoneally, N-acetylcys teine conjugates (mercapturates) of compound A (90 or 180 mu mol/kg) or glu tathione conjugates of compound A (180 mu mol/kg) with or without intraperi toneal pretreatments with aminooxyacetic acid (500 mu mol/kg) or acivicin ( 250 mu mol/kg). Rats were killed after 24 h, and kidney tissues were analyz ed for toxicity by histologic examination or for protein adducts by immunob lotting or immunohistochemical analysis, using antisera raised against the covalently bound thionoacyl halide metabolite of compound A. Results: Mercapturates and glutathione conjugates of compound A both produc ed renal corticomedullary necrosis similar to that caused by compound A. Am inooxyacetic acid, an inhibitor of renal cysteine conjugate beta-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibi tor of gamma-glutamyltranspeptidase, potentiated the toxicity of both class es of conjugates. No immunochemical evidence for renal protein adducts of t he thionacyl halide metabolite was found in rats 24 h after the administrat ion 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. Conclusion: The results of this study are consistent with the idea that a m echanism other than the renal cysteine conjugate beta-lyase pathway of meta bolic activation is responsible for the nephrotoxicity of compound A and it s glutathione and mercapturate conjugates in male Wistar rats.