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

Dolores B. Njoku, Lance R. Pohl, Edward A. Sokoloski, Michael R. Marchick, Craig B. Borkowf, Jackie L. Martin

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 β-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. Methods: Male Wistar rats were administered, intraperitoneally, N-acetylcysteine conjugates (mercapturates) of compound A (90 or 180 μmol/kg) or glutathione conjugates of compound A (180 μmol/kg) with or without intraperitoneal pretreatments with aminooxyacetic acid (500 μmol/kg) or acivicin (250 μmol/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. Results: 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 β-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibitor of γ-glutamyltranspeptidase, potentiated the toxicity of both classes of conjugates. No immunochemical evidence for renal protein adducts of the thionacyl halide metabolite v, as 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. Conclusion: The results of this study are consistent with the idea that a mechanism other than the renal cysteine conjugate β-lyase pathway of metabolic activation is responsible for the nephrotoxicity of compound A and its glutathione and mercapturate conjugates in male Wistar rats.

Original languageEnglish (US)
Pages (from-to)458-469
Number of pages12
JournalAnesthesiology
Volume90
Issue number2
DOIs
StatePublished - Feb 1 1999

Keywords

  • Bioactivation
  • Kidney
  • Molecular toxicity

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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