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 mumol/g wet tissue), whereas renal GSH levels were not changed. The role of hepatically derived GSH conjugates was investigated by administering the gamma-glutamyl-transpeptidase inhibitor, acivicin (20 mg/kg b.wt. i.p.). Treatment with acivicin led to a significant decrease in hepatic and renal gamma-glutamyltranspeptidase activity. Administration of acivicin 1 h before APAP administration protected against the alterations 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 of protein and glucose were decreased compared with rats not pretreated with acivicin. Hepatocellular damage (evaluated by glutamic pyruvic transaminase levels) induced by APAP was not altered by acivicin pretreatment. APAP plasma levels and its urinary excretion were the same whether the rats were pretreated with acivicin or not. A group of rats was fitted with an exteriorized biliary cannula before APAP administration to study the contribution of the biliary excretion route of APAP metabolites in the APAP-induced renal damage. No differences were observed on APAP-induced renal effects between rats cannulated or not. Our results suggest that hepatically derived APAP metabolites are partially responsible for APAP renal effects. The sinusoidal efflux of these metabolites is also suggested.