Nephrotoxicity of 4-amino-3-S-glutathionylphenol and its modulation by metabolism or transport inhibitors.

The nephrotoxicity of 4-amino-3-S-glutathionylphenol (PAP-GSH), a known metabolite of 4-amino-phenol (PAP), was determined in male Fischer 344 rats. Administration of a single dose of 40 or 60 mumol kg-1 caused a marked elevation in blood urea nitrogen and an increase in the urinary excretion of glucose, protein and gamma-glutamyltransferase (GGT). These changes were associated with histological alterations in the proximal tubule, where at the lower dose the lesion was restricted to the S3 region of the proximal tubule in the medullary rays, while at the higher dose the lesion extended to affect the S3 region in both the medullary rays and the outer stripe of the outer medulla. Studies with [35S]-PAP-GSH at 40 mumol kg-1 showed selective retention of radioactivity in the kidney, relative to other organs 24 h after dosing and that some radioactivity was covalently bound to renal proteins. Pretreatment of animals with probenecid, an inhibitor of renal organic anion transport, or aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, had little or no effect on the toxicity. In contrast, pretreatment of animals with acivicin, an inhibitor of gamma-glutamyltransferase, or co-administration of PAP-GSH with ascorbic acid almost completely protected against the nephrotoxicity. This protection was associated with a decreased concentration of radioactivity from [35S]-PAP-GSH in the kidneys and a decrease in the amount covalently bound to renal protein. Thus, the nephrotoxicity of PAP-GSH may be mediated by oxidation and further processing of the glutathione conjugate via gamma-glutamyltransferase.