THE CHEMISTRY OF PEROXYNITRITE - A PRODUCT FROM THE REACTION OF NITRIC-OXIDE WITH SUPEROXIDE

Nitric oxide and superoxide, which are produced by several cell types, rapidly combine to form peroxynitrite. This reaction can result in ni tric oxide scavenging, and thus mitigation of the biological effects o f superoxide. Also, superoxide can trap and hence modulate the effects of nitric oxide; superoxide dismutase, by controlling superoxide leve ls, therefore can influence the reaction pathways open to nitric oxide . The production of peroxynitrite, however, causes its own sequelae of events: Although neither (NO)-N-. nor superoxide is a strong oxidant, peroxynitrite is a potent and versatile oxidant that can attack a wid e range of biological targets. The peroxynitrite anion is relatively s table, but its acid, peroxynitrous acid (HOONO), rearranges to form ni trate with a half-life of similar to 1 s at pH 7, 37 degrees C. HOONO exists as a Boltzmann distribution of rotamers; at 5-37 degrees C HOON O has an apparent acidity constant, pK(a,app) of 6.8. Oxidation reacti ons of HOONO can involve two-electron processes (such as an SN2 displa cement) or a one-electron transfer (ET) reaction in which the substrat e is oxidized by one electron and peroxynitrite is reduced. These oxid ation reactions could involve one of two mechanisms. The first mechani sm is homolysis of HOONO to give HO. and (NO2)-N-., which initially ar e held together in a solvent cage. This caged pair of radicals (the '' geminate'' pair) can either diffuse apart, giving free radicals that c an perform oxidations, or react together either to form nitrate or to reform HOONO (a process called cage return). A large amount of cage re turn can explain the small entropy of activation (Arrhenius A-factor) observed for the decomposition of HOONO. A cage mechanism also can exp lain the residual yield of nitrate that appears to be formed even in t he presence of high concentrations of all of the scavengers studied to date, since scavengers capture only free HO. and (NO2)-N-. and not ca ged radicals. If the cage mechanism is correct, the rate of disappeara nce of peroxynitrite be slower in solvents of higher viscosity, and we do not find this to be the case. The second mechanism is that an acti vated isomer of peroxynitrous acid, HOONO can be formed in a steady s tate. The HOONO mechanism can explain the inability of,hydroxyl radic al scavengers to completely block either nitrate formation or the oxid ation of substrates such as methionine, since HOONO would be less rea ctive, and therefore more selective, than the hydroxyl radical itself. Thus scavengers, which would capture all of the hydroxyl radicals, ca pture only a portion of HOONO. The critical experiments necessary to distinguish the cage from the HOONO mechanism are discussed; of the t wo mechanisms, at present we prefer the HOONO mechanism.