Hepatotoxicity of acetaminophen in neonatal and young rats. II. Metabolic aspects

The effects of a toxic dose of acetaminophen on levels of hepatic glutathione and [14C]acetaminophen-derived metabolites covalently bound to tissue macromolecules were investigated in 11- (1000 mg/kg), 19- (750 mg/kg), and 33-day-old (1250 mg/kg) rats. Although hepatic glutathione levels are lower in untreated 11- and 19-day-old rats compared to 33-day-old animals, a toxic dose of acetaminophen produced similar maximal depletion in all ages (to 0.5 mg/g). Covalent binding of [14C]acetaminophen to hepatic and renal macromolecules was higher in the younger animals. Glutathione-derived conjugates of APAP were present in the liver and kidney of neonatal and young rats given a toxic dose of the drug. In addition, age-related differences in the levels of the sulfate and glucuronide conjugates of the drug in these tissues were observed. The data presented suggest that neonatal rats, while less susceptible than older rats to the hepatic necrosis produced by the drug, are more able to metabolically activate a toxic dose of acetaminophen.