Acetaminophen (APAP; N-acetyl-p-aminophenol), a commonly used analgesic/antipyretic drug, when overdosed, produces a centrilobular hepatic necrosis and hepatotoxicity driven predominantly by oxidative stress. Agarwal et al. studied the role of neuronal nitric-oxide synthase (nNOS) in APAP-induced hepatotoxicity in nNOS knockout (KO) and wild-type (WT) mice. APAP toxicity induced significant increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in WT mice as early as 4 h after dosing, whereas in nNOS KO mice, the increases were significantly delayed, occurring 8 h after dosing. However, there was no difference between WT and nNOS KO mice in terms of the ultimate histopathology of APAP hepatotoxicity. Because oxidative stress is regulated by manganese superoxide dismutase (MnSOD), it is interesting that MnSOD is the only nitrated protein in nNOS KO mice, which suggests that nitration of MnSOD is dependent on other NOS forms in the liver. Decreased MnSOD activity coincides with increased nitration of MnSOD and increased ALT release, suggesting that inhibition of MnSOD activity in APAP toxicity contributes to toxicity. These results indicate that the delay in the onset of hepatotoxicity in the nNOS KO mice compared with the WT mice suggests that nNOS plays an important role in initiation of APAP hepatotoxicity.

See article at J Pharmacol Exp Ther 2012, 340:134–142

• Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics