Regulation of nitric oxide synthesis in the liver.

Nitric oxide signalling during the past two decades has been one of the most rapidly growing areas in biology. This simple free radical gas can regulate an ever-growing list of biological processes. Here the regulation of NO synthesis in the liver is reviewed. The biogenesis of nitric oxide (NO) is catalysed by nitric oxide synthases (NOS). These enzymes catalyse the oxidation of one of the guanidino nitrogens of l-arginine by molecular oxygen to form NO and citrulline. Three NOS have been identified: two constitutive (cNOS: type 1 or neuronal and type 3 or endothelial) and one inducible (iNOS: type 2). As to the liver, cNOS activity is normally detectable in Kupffer cells, whereas no cNOS is ever encoded in hepatocytes. However, hepatocytes, Kupffer and stellate cells (the three main types of liver cells) are prompted to express an intense iNOS activity once exposed to effective stimuli such as bacterial lipopolysaccharide and cytokines. This review is focused mainly on two aspects: regulation of NOS activity and expression by endogenous and exogenous compounds. Because NO production has beneficial and detrimental effects, understanding the molecular mechanisms that govern NOS is critical to developing strategies to manipulate NO production in liver diseases. Copyright 2000 John Wiley & Sons, Ltd.