Decreased hepatotoxicity of acetaminophen in mice lacking inducible nitricoxide synthase

Nitric oxide (NO) is a cytotoxic inflammatory mediator known contribute to hepatotoxicity. NO is produced by both parenchymal and nonparenchymal cells in response to inflammatory mediators via inducible nitric oxide synthase (NOSII). In the present studies we analyzed the role of NO in the hepatotox icity of acetaminophen (AA). Administration of a toxic dose of AA to rats ( 1 g/kg) resulted in increased NO production by both liver macrophages (MP) and hepatocytes (HC). This was correlated with increased NOSII protein and mRNA expression in the liver. To determine if NO contributes to toxicity, w e used knockout mice lacking NOSII. Treatment of wild type control mice wit h AA (100-300 mg/kg, ip) resulted in a dose and Lime dependent induction of centrilobular necrosis which was evident within 6 hr. This was associated with a marked increase in serum transaminase levels. Mice lacking NOSII wer e significantly less sensitive to the hepatotoxic effects of AA than were c ontrol mice. These data together with our previous findings that blocking N O production by administration of a specific NOSII inhibitor abrogated AA h epatotoxicity demonstrate that NO produced via NOSII is involved in the pat hogenesis of liver injury.