Biosynthesis, Physiological Disposition, and Biochemical Effects of Nephrotoxic Glutathione and Cysteine S-Conjugates
Annual technical rept. 15 Aug 1986-23 Jul 1987
ROCHESTER UNIV MEDICAL CENTER NY DEPT OF PHARMACOLOGY
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The nephrotoxicity of certain halogenated alkanes and alkenes is the result of hepatic glutathione S-conjugate formation, followed by renal metabolism of the conjugates to corresponding cysteine S-conjugates, which then undergo renal bioactivation to the ultimate toxic species. These experiments have used synthetic PCBG as the substrate and hepatic microsomal fractions as the source of enzyme. Results indicate that PCBG is a substrate for microsomal transferases with the reaction being time-dependent, protein-dependent, PCBG-dependent and dependent upon glutathione concentrations. Methods to study the alkylation of renal DNA have been devised with sulfides I-IV being isolated to allow generation of putative reaction intermediates in high yield. Predictions can be made that the sulfide will be cytotoxic to isolated rat hepatocytes. PCBG inhibits renal mitochondrial DNA synthesis and the effect is concentration dependent and inhibited by aminooxyacetic acid. The effect of DNA degradation is being investigated.