Nephrotoxicity of acetaminophen in male Wistar rats: role of hepatically derived metabolites

The role of hepatically derived metabolites was studied in rats treated with a nephrotoxic dose of acetaminophen (APAP, 1000 mg/kg b.wt. i.p.). Hepatic glutathione (GSH) content 16 h after APAP dosing was significantly decreased (control = 3.83 ± 0.1, APAP = 2.51 ± 0.3 .tmol/g wet tissue), whereas renal GSH levels were not changed. The role of hepatically derived GSH conjugates was investigated by administering the y-glutamyl-transpeptidase inhibitor, acivicin (20 mg/kg b.wt. i.p.). Treat-ment with acivicin led to a significant decrease in hepatic and renal y-glutamyltranspeptidase activity. Administration of acivi-cm 1 h before APAP administration protected against the alter-ations of glomerular filtration rate and urea and creatinine plasma levels induced by APAP. The appearance of epithelial cells and granular casts as well as the urinary excretion o