Nitric oxide and peroxynitrite. The ugly, the uglier and the not so good -A personal view of recent controversies

Nitric oxide, a gaseous free radical, is poorly reactive with most biomolec ules but highly reactive with other free radicals. Its ability to scavenge peroxyl and other damaging radicals may make it an important antioxidant in vivo, particularly in the cardiovascular system, although this ability has been somewhat eclipsed in the literature by a focus on the toxicity of per oxynitrite, generated by reaction of O-2(.-) with NO. (or of NO- with O-2) On balance, experimental and theoretical data support the view that ONOO- c an lead to hydroxyl radical (OH.) generation at pH 7.4, but it seems unlike ly that OH. contributes much to the cytotoxicity of ONOO-. The cytotoxicity of ONOO- may have been over-emphasized: its formation and rapid reaction w ith antioxidants may provide a mechanism of using NO . to or even of using O-2(.) to dispose of dispose of excess O-2(.-) excess NO., in order to main tain the correct balance between these radicals in vivo. Injection or insti llation of "bolus" ONOO- into animals has produced tissue injury, however, although more experiments generating ONOO- at steady rates in vivo are requ ired. The presence of S-nitrotyrosine in tissues is still frequently taken as evidence of ONOO- generation in vivo but abundant evidence now exists to support the view that it is a biomarker of several "reactive nitrogen spec ies" Another under-addressed problem is the reliability of assays used to d etect and measure 3-nitrotyrosine in tissues and body fluids: immunostainin g results vary between laboratories and simple HPLC methods are susceptible to artefacts. Exposure of biological material to low pH (e.g. during acidi c hydrolysis to liberate nitrotyrosine from proteins) or to H2O2 might caus e artefactual generation of nitrotyrosine from NO2- in the samples. This ma y be the origin of some of the very large values for tissue nitrotyrosine l evels quoted in the literature. Nitrous acid causes not only tyrosine nitra tion but also DNA base deamination at low pH: these events are relevant to the human stomach since saliva and many foods are rich in nitrite. Several plant phenolics inhibit nitration and deamination in vitro, an effect that could conceivably contribute to their protective effects against gastric ca ncer development.