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 metabolite DCVC sulfoxide (DCVCO) on renal function in vivo and in vitro were investigated to assess the role of sulfoxidation in the mechanism of toxicity of cysteine S-conjugates. Both conjugates were potent nephrotoxicants in rats in vivo, but at equimolar doses, DCVCO produced greater renal injury (i.e., increases in blood urea nitrogen levels and anuria and more severe and widespread proximal tubular necrosis) than DCVC. Pretreatment of rats with aminooxyacetic acid (AOAA), a selective cysteine conjugate beta-lyase (beta-lyase) inhibitor, did not protect against DCVCO nephrotoxicity, whereas rats given DCVC and AOAA exhibited partial protection. These results suggest that in addition to cleavage by the beta-lyase, sulfoxidation by the cysteine conjugate S-oxidase (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 was made to correlate in vitro cytotoxicity with the cellular distribution of the beta-lyase and S-oxidase. The finding that beta-lyase activity exhibited a 2-fold higher Vmax/Km ratio in PT cells than in DT cells, the greater inhibition of both beta-lyase activity and DCVC toxicity 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 importance 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, provide further evidence for DCVC bioactivation by S-oxidase.(ABSTRACT TRUNCATED AT 250 WORDS)
Lash
L H
LH
Department of Pharmacology, Wayne State University, School of Medicine, Detroit, Michigan.
Sausen
P J
PJ
Duescher
R J
RJ
Cooley
A J
AJ
Elfarra
A A
AA
D000818:Animals; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D050558:Cysteine Dioxygenase; D049308:Dioxygenases; D004789:Enzyme Activation / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000201:enzymology; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008190:Lyases / Q000378:metabolism / Q000502:physiology*; D008297:Male; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013454:Sulfoxides / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
D013454:Sulfoxides; C039961:S-(1,2-dichlorovinyl)cysteine; D010105:Oxygenases; D049308:Dioxygenases; D050558:Cysteine Dioxygenase; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019971:cysteine lyase; D003545:Cysteine