N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in human hepatocytes

Background/Aims: A major role has been described for inducible nitric oxide (NO) synthase in several chronic inflammatory liver diseases. N-Acetyl-cysteine (NAC) is a sulfhydryl donor molecule with antioxidant and antiinflammatory effects. It attenuates NO generation following lipopolysaccharide injection in rats. Our goal was to study the effect of NAC on NO synthase induction in hepatocytes in response to proinflammatory cytokines. Methods: The effect of NAC on NO synthase induction was studied in the human hepatocyte cell lines HepG2 and 2.2.15 treated with a mixture of proinflammatory cytokines. Interactions between NAC and cytokines on nuclear factor-kappaB (NF-kappaB) activation and NO synthase promoter transactivation were investigated. Results: NAC dose-dependently modulated the induction of NO synthase mRNA expression, the release of nitrites and the formation of NF-kappaB binding complexes in cytokine-treated hepatocytes. NAC also reduced the transactivation of the NO synthase promoter. Conclusions: Our data show that exposure of hepatocytes to NAC modulated NO synthase expression and NF-kappaB activity, the key responses of the hepatocyte to inflammatory mediators. These data constitute preliminary evidence that NAC might have hepatoprotective actions of potential relevance in chronic inflammatory liver diseases, mediated partially through the modulation of NO production. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.