N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in human hepatocytes.
OBJECTIVE
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.
Majano
Pedro Lorenzo
PL
Unidad de Hepatología (planta 3), Hospital Universitario de la Princesa, Universidad Autónoma, Diego de León 62, E-28006 Madrid, Spain.
Medina
Jesús
J
Zubía
Itxaso
I
Sunyer
Lourdes
L
Lara-Pezzi
Enrique
E
Maldonado-Rodríguez
Alejandra
A
López-Cabrera
Manuel
M
Moreno-Otero
Ricardo
R
D000111:Acetylcysteine / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D000111:Acetylcysteine