iNOS-mediated nitric oxide production and its regulation.

This review focuses on the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and its regulation under physiological and pathophysiological conditions. NO is an important biological mediator in the living organism that is synthesized from L-arginine using NADPH and molecular oxygen. However, the overproduction of NO which is catalyzed by iNOS, a soluble enzyme and active in its dimeric form, is cytotoxic. Immunostimulating cytokines or bacterial pathogens activate iNOS and generate high concentrations of NO through the activation of inducible nuclear factors, including NFkB. iNOS activation is regulated mainly at the transcriptional level, but also at posttranscriptional, translational and postranslational levels through effects on protein stability, dimerization, phosphorylation, cofactor binding and availability of oxygen and L-arginine as substrates. The prevention of the overproduction of NO in the living organism through control of regulatory pathways may assist in the treatment of high NO-mediated disorders without changing physiological levels of NO. Copyright 2004 Elsevier Inc.