Metabolic activation and detoxication of nephrotoxic cysteine and homocysteine S-conjugates.

AUTOR(ES)

Elfarra, A A

RESUMO

S-(1,2-Dichlorovinyl)-L-homocysteine (DCVHcy), an analogue of the nephrotoxin S-(1,2-dichlorovinyl)-L-cysteine (DCVCys), is a much more potent nephrotoxin than DCVCys both in vivo and in isolated renal proximal tubular cells. S-(1,2-Dichlorovinyl)-DL-alpha-methylhomocysteine, at equimolar doses relative to DCVHcy, is not nephrotoxic. Agents that inhibit pyridoxal phosphate-dependent enzymes (DL-propargylglycine and aminooxyacetic acid) or renal organic anion transport (probenecid) protect against DCVHcy-induced nephrotoxicity. With kidney cytosol, DCVHcy or the analogue S-(2-benzothiazolyl)-L-homocysteine (BTHcy) is not metabolized to 2-ketobutyrate, but 2-mercaptobenzothiazole is a metabolite of BTHcy and the Vmax for its formation is enhanced by addition of 2-ketobutyrate. These results are consistent with a bioactivation mechanism for DCVHcy that involves enzymatic deamination followed by a nonenzymatic beta-elimination to produce two reactive intermediates--i.e., S-(1,2-dichlorovinyl)thiol and 2-keto-3-butenoic acid. The Km values for the N-acetylation of DCVCys and DCVHcy by kidney microsomal N-acetyltransferase are similar, but the rate of DCVCys N-acetylation is 4-fold greater than the rate measured with DCVHcy as the substrate. Thus, the remarkable nephrotoxic potency of DCVHcy compared with DCVCys may be attributable to intrarenal differences in activation and detoxication.

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