Glutathione conjugate formation, a major metabolic pathway for a variety of chemicals, is frequently considered as a detoxication reaction. Current evidence, however, has implicated glutathione and cysteine conjugate formation in the nephrotoxicity and carcinogenicity of halogenated hydrocarbons, chemicals which are widely used industrially and have been found to be major environmental pollutants. Recently, we have provided evidence for the existence of a novel NADPH-dependent cysteine conjugate S-oxidase activity in rat hepatic and renal microsomes which converts cysteine S-conjugates into sulfoxides and appears to be associated with flavin-containing monooxygenases rather than cytochrome P450-dependent enzymes. Preliminary studies have also shown that the sulfoxide form of the model S-vinyl conjugate, S-(1,2-Dichlorovinyl)-L-cysteine, is more nephrotoxic to rats than the sulfide form. S-(1,2-Dichlorovinyl)-L- cysteine sulfoxide acts as a Michael acceptor in its reaction with glutathione both in vitro and in vivo. Because these studies indicate that cysteine conjugate S-oxidase may play an important role in the nephrotoxicity and carcinogenicity of S-conjugates, the broad objectives of the proposed research are to determine the role of sulfoxidation in glutathione and cysteine S-conjugate-induced toxicity. Specific experimental objectives are as follows: l) To isolate and characterize rat hepatic and renal microsomal cysteine conjugate S- oxidases; 2) To determine the substrate specificity of cysteine conjugate S-oxidases; 3) To investigate the relative roles of cysteine conjugate S- oxidase and cysteine conjugate beta-lyase in the metabolism and toxicity of S-conjugates. [This will include in vivo metabolism and disposition studies with model cysteine S-conjugates and their corresponding sulfoxides, and histopathological and functional assessment of liver and kidney after male and female rats are given nephrotoxic S-conjugates and their corresponding sulfoxides].
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