ROLES OF CYSTEINE CONJUGATE BETA-LYASE AND S-OXIDASE IN NEPHROTOXICITY - STUDIES WITH S-(1,2-DICHLOROVINYL)-L-CYSTEINE AND S-(1,2-DICHLOROVINYL)-L-CYSTEINE SULFOXIDE

Effects of S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and its putative me tabolite DCVC sulfoxide (DCVCO) on renal function in vivo and in vitro were investigated to assess the role of sulfoxidation in the mechanis m of toxicity of cysteine S-conjugates. Both conjugates were potent ne phrotoxicants in rats in vivo, but at equimolar doses, DCVCO produced greater renal injury (i.e., increases in blood urea nitrogen levels an d anuria and more severe and widespread proximal tubular necrosis) tha n DCVC. Pretreatment of rats with aminooxyacetic acid (AOAA), a select ive cysteine conjugate beta-lyase (beta-lyase) inhibitor, did not prot ect against DCVCO nephrotoxicity, whereas rats given DCVC and AOAA exh ibited partial protection. These results suggest that in addition to c leavage by the beta-lyase, sulfoxidation by the cysteine conjugate S-o xidase (S-oxidase) may play a role in DCVC nephrotoxicity. In isolated rat kidney proximal tubular (PT) and distal tubular (DT) cells, both DCVC and DCVCO produced time- and concentration-dependent increases in the release of lactate dehydrogenase. Because DCVC was generally more toxic in PT cells and DCVCO was more toxic in DT cells, an attempt wa s made to correlate in vitro cytotoxicity with the cellular distributi on of the beta-lyase and S-oxidase. The finding that beta-lyase activi ty exhibited a 2-fold higher V-max/K-m ratio in PT cells than in DT ce lls, the greater inhibition of both beta-lyase activity and DCVC toxic ity by AOAA in PT cells than in DT cells and the lower (40%) S-oxidase activity in PT cells than in DT cells provide evidence for the import ance of the beta-lyase in DCVC toxicity in PT cells. The finding that DCVCO was more toxic in DT cells than in PT cells and the inability of AOAA to protect DT cells from DCVC-induced cytotoxicity, however, pro vide further evidence for DCVC bioactivation by S-oxidase. Therefore, the S-oxidase pathway may play a role in DCVC nephrotoxicity and may, in part, explain the incomplete in vivo protection against DCVC nephro toxicity by AOAA.