Acetaminophen nephrotoxicity in male Wistar rats

Acute acetaminophen (APAP) nephrotoxicity was studied in male Wistar rats 1 h after different APAP single doses (200, 500 and 1000 mg/kg body wt, i.p.). Significant impairments in glomerular filtration rate (GFR) and clearance of p-aminohippuric acid (ClPAH) were observed in a dose-dependent way, although tubular parameters measured, water and electrolyte fractional excretion, remained at control values, while the urine to plasma osmolality ratios (Uosm/Posm) were diminished in APAP-1000 rats (control = 2.93 +/- 0.20, APAP-1000 = 1.40 +/- 0.04). The time course of renal function was also studied in APAP-1000 mg/kg-treated animals; parallel impairments were observed in GFR, ClPAH and tubular functions. Maximal alteration was observed at 16 h and restorement began at 24 h post-injection. Glucose renal handling, either at low or at high tubular glucose loads, remained at control values. Thus, our data suggest that the early stage of acetaminophen nephrotoxicity might be due to renal hemodynamic changes which might induce an alteration in tubular function principally in distal structures of medullary tissue, as shown by the Uosm/Posm results. These effects occurred coupled with a diminution in hepatic glutathione (GSH) levels at every APAP dose and in renal GSH levels in APAP-1000 mg/kg-treated rats. Moreover, renal damage was observed both in the presence or absence of hepatic damage.