INCREASED RESISTANCE OF DIABETIC RATS TO ACETAMINOPHEN-INDUCED HEPATOTOXICITY

  • 1 January 1982
    • journal article
    • research article
    • Vol. 220  (3) , 504-513
Abstract
The effects of insulin-deficient diabetes on acetaminophen-induced hepatotoxicity and metabolism were investigated in streptozotoxin-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; 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. Evidently, insulin-deficient diabetic male rats 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.