Gl. Squadrito et Wa. Pryor, OXIDATIVE CHEMISTRY OF NITRIC-OXIDE - THE ROLES OF SUPEROXIDE, PEROXYNITRITE, AND CARBON-DIOXIDE, Free radical biology & medicine, 25(4-5), 1998, pp. 392-403
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.