title: Increased resistance of diabetic rats to acetaminophen-induced hepatotoxicity.
abstract: The effects of insulin-deficient diabetes on acetaminophen-induced hepatotoxicity and metabolism were investigated in streptozotocin-treated male rats. Diabetic rats were less susceptible to acetaminophen-induced liver injury than normal rats. The protective effect was reversed by the administration of insulin. Diabetic rats metabolized acetaminophen at a faster rate than normal rats, as evidenced by a shorter blood half-life. Pharmacokinetic studies revealed that the increased metabolic clearance was largely the result of a markedly enhanced glucuronidation capacity. The rate of formation of acetaminophen sulfate was also modestly increased in diabetic animals, whereas the apparent rate of the toxic pathway was approximately equal in both normal and diabetic animals. Steady-state levels of hepatic glutathione were significantly higher in diabetic rats. After a large dose of acetaminophen, the rate and relative amount of hepatic glutathione depletion were similar in both groups; however, the absolute amount of glutathione was always greater in diabetic animals. These data indicate that insulin-deficient diabetic male rat are more resistant to acetaminophen-induced hepatotoxicity as a result of an increased capacity to eliminate the drug as the nontoxic glucuronide and sulfate conjugates and an increased glutathione-dependent detoxification capacity.
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats
chemical_list: D005965:Glucuronates; D000082:Acetaminophen; D005978:Glutathione; D005947:Glucose