Age-related increased susceptibility of male Fischer 344 rats to acetaminophen nephrotoxicity

Abstract

Male Fischer 344 rats classified as young (2–4 months), middle-aged (12–14 months) and aged (22–25 months) received 300, 600 or 800 mg/kg acetaminophen (APAP) intraperitoneally and were sacrified 24 hr later. Blood urea nitrogen (BUN) concentration and urinary glucose and osmolality were determined. In addition, kidneys were evaluated for histopathological changes. APAP did not affect osmolality or BUN concentrations and failed to produce lesions after any dose in young rats. Osmolality was decreased 40% and 50% in middle-aged and aged rats, respectively, after 800 mg/kg APAP. Glucosuria was prominent in aged rats after the 600 and 800 mg/kg doses were administered, while middle-aged rats showed little glucosuria after these doses. BUN concentrations were elevated 89% and 183% in middle-aged and aged rats, respectively, given 600 mg/kg APAP; after 800 mg/kg, BUN concentrations were elevated approximately four-fold in both age groups. Pathological evaluations showed a greater incidence of acute tubular necrosis (ATN) in aged kidneys compared to kidneys of middle-aged rats after 600 mg/kg, while the two older groups exhibited similar, more severe ATN after 800 mg/kg APAP. These data suggest an age-related increased susceptibility of male Fisher 344 rats to APAP nephrotoxicity.