OXIDATIVE CHEMISTRY OF NITRIC-OXIDE - THE ROLES OF SUPEROXIDE, PEROXYNITRITE, AND CARBON-DIOXIDE

The roles of superoxide (O-2(.-)), peroxynitrite, and carbon dioxide i n the oxidative chemistry of nitric oxide ((NO)-N-.) are reviewed. The formation of peroxynitrite from (NO)-N-. and O-2(.-) is controlled by superoxide dismutase (SOD), which can lower the concentration of supe roxide ions. The concentration of CO2 in vivo is high (ca. 1 mM), and the rate constant for reaction of CO2 with -OONO is large (pH-independ ent k = 5.8 x 10(4) M(-1)s(-1)). Consequently, the rate of reaction of peroxynitrite with CO, is so fast that most commonly used scavengers would need to be present at very high, near toxic levels in order to c ompete with peroxynitrite for CO,. Therefore, in the presence of physi ological levels of bicarbonate, only a limited number of biotargets re act directly with peroxynitrite. These include heme-containing protein s such as hemoglobin, peroxidases such as myeloperoxidase, seleno-prot eins such as glutathione peroxidase, proteins containing zinc-thiolate centers such as the DNA-binding transcription factors, and the synthe tic antioxidant ebselen. The mechanism of the reaction of CO, with -OO NO produces metastable nitrating, nitrosating, and oxidizing species a s intermediates. An analysis of the lifetimes of the possible intermed iates and of the catalysis of peroxynitrite decompositions suggests th at the reactive intermediates responsible for reactions with a variety of substrates may be the free radicals (NO2)-N-. and CO3.-. Biologica lly important reactions of these free radicals are, for example, the n itration of tyrosine residues. These nitrations can be pathological, b ut they also may play a signal transduction role, because nitration of tyrosine can modulate phosphorylation and thus control enzymatic acti vity. In principle, it might be possible to block the biological effec ts of peroxynitrite by scavenging the free radicals (NO2)-N-. and CO3. -. Because it is difficult to directly scavenge peroxynitrite because of its fast reaction with CO2, scavenging of intermediates from the pe roxynitrite/CO2 reaction would provide an additional way of preventing peroxynitrite-mediated cellular effects. The biological effects of pe roxynitrite also can be prevented by limiting the formation of peroxyn itrite from (NO)-N-. by lowering the concentration of O-2(.-) using SO D or SOD mimics. Increased formation of peroxynitrite has been linked to Alzheimer's disease, rheumatoid arthritis, atherosclerosis, lung in jury, amyotrophic lateral sclerosis, and other diseases. (C) 1998 Else vier Science Inc.