Mechanism of S-(1,2-dichlorovinyl)glutathione-induced nephrotoxicity.
S-(1,2-Dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-DL-cysteine are potent nephrotoxins. Agents that inhibit gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and renal organic anion transport systems, namely L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), aminooxyacetic acid, and probenecid, respectively, protected against S-conjugate-induced nephrotoxicity. Furthermore, S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine, which cannot be cleaved by cysteine conjugate beta-lyase, was not nephrotoxic. These results strongly support a role for renal gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and organic anion transport systems in S-(1,2-dichlorovinyl)glutathione- and S-(1,2-dichlorovinyl)cysteine-induced nephrotoxicity.
Elfarra
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Jakobson
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I
Anders
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MW
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001806:Blood Urea Nitrogen; D013437:Carbon-Sulfur Lyases; D003545:Cysteine / Q000031:analogs & derivatives / Q000633:toxicity; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D006029:Glycosuria / Q000139:chemically induced; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008190:Lyases / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013347:Subcellular Fractions / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D007555:Isoxazoles; D000625:Aminooxyacetic Acid; C039961:S-(1,2-dichlorovinyl)cysteine; C041464:S-(1,2-dichlorovinyl)glutathione; D005723:gamma-Glutamyltransferase; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D005978:Glutathione; D003545:Cysteine; C006303:acivicin; D011339:Probenecid