Nephrotoxicity of S-(2-chloroethyl)glutathione in the Fischer rat: evidence for gamma-glutamyltranspeptidase-independent uptake by the kidney.
S-(2-chloroethyl)glutathione (CEG; 270 mumol/kg) produced renal lesions that were confined to the proximal tubules of the outer stripe of the outer medulla and were similar to those lesions produced by the cysteine analog S-(2-chloroethyl)cysteine or by the nephrotoxic glutathione (GSH) adduct of 2-bromohydroquinone. These histopathologic changes in the kidney were correlated with alterations in renal function as reflected by dose- and time-dependent elevations in blood urea nitrogen levels as well as by the increased urinary excretion of protein, glucose and lactate dehydrogenase activity. The role of renal GSH metabolism as a mediating factor in the nephrotoxicity of these GSH conjugates was investigated by administering the gamma-glutamyltranspeptidase inhibitor AT-125 [L-(alpha-S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid]. Treatment with AT-125 led to a dose-dependent decrease in renal gamma-glutamyltranspeptidase activity that correlated inversely with increased GSH concentrations in the urine and kidney. Pretreatment with AT-125 ameliorated 2-bromohydroguinone-induced renal toxicity but did not protect against the CEG-induced renal lesion. In fact, pretreatment with AT-125 produced a dose-dependent potentiation of CEG renal toxicity. The CEG-induced renal lesion was dependent on a probenecid-sensitive transport system that was not involved in the toxicity of 2-bromohydroguinone. These studies demonstrate that CEG need not be metabolized by gamma-glutamyltranspeptidase to the corresponding cysteine adduct [S-(2-chloroethyl)cysteine] in order to enter renal tubule cells and ultimately exert its nephrotoxic action.
D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000506:poisoning / Q000652:urine; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009399:Nephrons / Q000187:drug effects*; D009994:Osmolar Concentration; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000506:poisoning; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D007555:Isoxazoles; D013438:Sulfhydryl Compounds; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin; C046570:S-(2-chloroethyl)glutathione; D011339:Probenecid