title: Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat.
abstract: The effects of an acute fast on acetaminophen metabolism and hepatotoxicity were investigated in male Long Evans Hooded rats. Histologic studies confirmed that fasting potentiated acetaminophen-induced hepatic necrosis. The previous known fasting-induced decrease in hepatic levels of glutathione and depletion of glycogen levels were also confirmed. Pharmacokinetic studies revealed that, at high dose levels of acetaminophen, fasting decreased the overall rate of elimination as evidence by a longer blood half-life of the drug. The decreased clearance was largely the result of decreases in the apparent rate constants for glucuronidation (ca. 40%) and for sulfation (ca. 30%). Fasting had no significant effects on the apparent rate constants for formation of either acetaminophen mercapturate or the methylthio derivatives. The depression of the nontoxic glucuronidation and sulfation pathways resulted in an increased proportion of the dose converted to the toxic metabolite and, hence, contributed to the potentiation of liver injury in fasted rats. In addition, these studies demonstrated that significant glucuronidation capacity (ca. 60% of that in fed rats) was maintained in fasted rats, indicating that: the glucuronidation capacity was not directly correlated with glycogen levels; and in fasted rats the glucose required for UDP-glucuronic acid formation for acetaminophen glucuronidation was supplied from sources other than glycogen.
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D004357:Drug Synergism; D005215:Fasting; D005965:Glucuronates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D009336:Necrosis; D051381:Rats
chemical_list: D005965:Glucuronates; D008112:Liver Glycogen; D000082:Acetaminophen; D005978:Glutathione