Nitric Oxide Pathways in Toxic Responses

AbstractThe host response to chemically induced tissue injury is complex, involving a variety of cell types and soluble mediators. One of the most intensely investigated mediators implicated in the pathogenic process is nitric oxide, a highly reactive small‐molecular‐weight gas. Almost all cells in the body have the capacity to generate nitric oxide fromL‐arginine via one of three isoforms of the enzyme, nitric oxide synthase. These include the high‐output isoform, inducible nitric oxide synthase, and the low‐output isoforms, endothelial and neuronal nitric oxide synthases. Toxicants stimulate production of nitric oxide in target tissues by up‐regulating expression and/or activity of nitric oxide synthases. This can occur directly by reaction of the chemicals or their metabolites with target cells, or indirectly, via cytokines, growth factors and lipid mediators generated following tissue injury. Whereas low levels of nitric oxide function to activate biochemical and molecular signalling cascades in target cells, high levels induce nitrosative stress. Both of these actions can contribute to toxicity. Selective pharmacological inhibitors and knockout mice have been used to delineate the role of the different isoforms of nitric oxide synthase in chemical toxicity. Further studies on the pathways by which excessive production of reactive nitrogen species leads to pathology will be key for a more complete understanding of the mechanisms of xenobiotic‐induced cytotoxicity and tissue injury.