Role of nitric oxide in hepatotoxicity

Ingestion of toxic doses of acetaminophen causes acute Liver failure accompanied by centrilobular hepatic necrosis. Although covalent binding of reactive acetaminophen metabolites is known to initiate liver damage, reactive oxygen and nitrogen intermediates released by parenchymal and nonparenchymal cells may also contribute to toxicity. In the present studies, we evaluated the role of reactive nitrogen intermediates in acetaminophen-induced hepatotoxicity. Treatment of male Long Evans Hooded rats (120 g) with acetaminophen (1 g/kg, i.p) results in centrilobular hepatic necrosis. This was correlated with increased serum transaminase levels and expression of inducible nitric oxide synthase protein and mRNA as determined by immunohistochemistry and in situ hybridization. Hepatocytes isolated from control rats were found to produce nitric oxide in response to interferon-gamma(IFN-gamma) but not to lipopolysaccharide (LPS). Following acetaminophen treatment of rats, hepatocytes produced more nitric oxide in response to low levels of IFN-gamma than did control cells. In addition, these cells were sensitized to produce nitric oxide in response to LPS. To analyze the role of nitric oxide in acetaminophen-induced hepatotoxicity, we used aminoguanidine, a specific inhibitor of inducible nitric oxide synthase (iNOS). Pretreatment of rat with aminoguanidine prevented acetaminophen-induced hepatic necrosis as well as increases in serum transaminase levels. Interestingly, aminoguanidine treatment in vivo also blocked expression of iNOS protein and mRNA in the liver. These data suggest that nitric oxide is an important mediator in acetaminophen-induced hepatotoxicity. Moreover, it appears that nitric oxide regulates iNOS activity in an autocrine manner in the liver.