Additive protection of cimetidine and N-acetylcysteine treatment against acetaminophen-induced hepatic necrosis in the rat

Cimetidine protects against acetaminophen hepatotoxicity in the rat as evidenced by improved survival, lower serum aminotransferases, improved liver histology, decreased in vivo and in vitro covalent binding of acetaminophen to liver protein and decreased rate of glutathione depletion. This protection is best explained by inhibition of acetaminophen oxidation by cimetidine. N-acetylcysteine, the accepted antidote, protects against acetaminophen hepatotoxicity primarily by enhancing glutathione synthesis. Inhibition of acetaminophen oxidation by cimetidine has been demonstrated directly in vitro with both rat and human liver microsomes. The aim of the present study was to determine whether cimetidine and N-acetylcysteine might be additive in their protection against acetaminophen hepatotoxicity as cimetidine and N-acetylcysteine have different mechanisms of protection action. Treatment with either cimetidine or N-acetylcysteine improved survival and serum transaminases in a dose-related manner but protection by the combination was additive when compared to each agent alone. Cimetidine decreased the rate of hepatic glutathione depletion and acetaminophen covalent binding in vivo in a dose-dependent manner whereas only a high dose of N-acetylcysteine decreased covalent binding. However, the combination of cimetidine and N-acetylcysteine more effectively prevented glutathione depletion and covalent binding in vivo than either agent used alone. We conclude that protection against acetaminophen hepatotoxicity using a combination of cimetidine and N-acetylcysteine is better than that found with either agent alone. Inasmuch as cimetidine does not increase hepatic glutathione per se, or does N-acetylcysteine inhibit acetaminophen oxidation, the additive protection against acetaminophen hepatotoxicity is best explained by the above mentioned mechanisms of action for each agent.