Cytotoxicity of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine in isolated rat kidney cells.
S-(1,2-Dichlorovinyl)glutathione (DCVG) and S-(1,2-dichlorovinyl)-L-cysteine (DCVC) produced time- and concentration-dependent cell death in isolated rat kidney proximal tubular cells. AT-125 blocked and glycylglycine potentiated DCVG toxicity, indicating that metabolism by gamma-glutamyltransferase is required. S-(1,2-Dichlorovinyl)-L-cysteinylglycine, a putative metabolite of DCVG, also produced cell death, which was prevented by 1,10-phenanthroline, phenylalanylglycine, and aminooxyacetic acid, inhibitors of aminopeptidase M, cysteinylglycine dipeptidase, and cysteine conjugate beta-lyase, respectively. Aminooxyacetic acid and probenecid protected against DCVC toxicity, indicating a role for metabolism by cysteine conjugate beta-lyase and organic anion transport, respectively. DCVC produced a small decrease in cellular glutathione concentrations and did not change cellular glutathione disulfide concentrations or initiate lipid peroxidation. DCVC caused a large decrease in cellular glutamate and ATP concentrations with a parallel decrease in the total adenine nucleotide pool; these changes were partially prevented by aminooxyacetic acid. Both DCVG and DCVC inhibited succinate-dependent oxygen consumption, but DCVC had no effect when glutamate + malate or ascorbate + N,N,N',N'-tetramethyl-p-phenylenediamine were the electron donors. DCVC inhibited mitochondrial, but not microsomal, Ca2+ sequestration. These alterations in mitochondrial function were partially prevented by inhibition of DCVG and DCVC metabolism and were strongly correlated with decreases in cell viability, indicating that mitochondria may be the primary targets of nephrotoxic cysteine S-conjugates.
D000227:Adenine Nucleotides / Q000378:metabolism; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D018826:CD13 Antigens; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006033:Glycylglycine / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D000227:Adenine Nucleotides; D004151:Dipeptides; D007555:Isoxazoles; D010618:Phenanthrolines; D006033:Glycylglycine; D000625:Aminooxyacetic Acid; C040500:phenylalanylglycine; C039961:S-(1,2-dichlorovinyl)cysteine; C041464:S-(1,2-dichlorovinyl)glutathione; D000626:Aminopeptidases; D018826:CD13 Antigens; D005978:Glutathione; D003545:Cysteine; C006303:acivicin; C025205:1,10-phenanthroline