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.[1]References
- Nephrotoxicity of S-(2-chloroethyl)glutathione in the Fischer rat: evidence for gamma-glutamyltranspeptidase-independent uptake by the kidney. Kramer, R.A., Foureman, G., Greene, K.E., Reed, D.J. J. Pharmacol. Exp. Ther. (1987) [Pubmed]
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