Gl. Squadrito et al., Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid, ARCH BIOCH, 376(2), 2000, pp. 333-337
Peroxynitrite, a biological oxidant formed from the reaction of nitric oxid
e with the superoxide radical, is associated with many pathologies, includi
ng neurodegenerative diseases, such as multiple sclerosis (MS), Gout (hyper
uricemic) and MS are almost mutually exclusive, and uric acid has therapeut
ic effects in mice with experimental allergic encephalomyelitis, an animal
disease that models MS, This evidence suggests that uric acid may scavenge
peroxynitrite and/or peroxynitrite-derived reactive species. Therefore, we
studied the kinetics of the reactions of peroxynitrite with uric acid from
pH 6.9 to 8.0, The data indicate that peroxynitrous acid (HOONO) reacts wit
h the uric acid monoanion with k = 155 M-1 s(-1) (T = 37 degrees C, pH 7.4)
giving a pseudo-first-order rate constant in blood plasma k(Uratc/plasma)
= 0.05 s(-1) (T = 37 degrees C, pH 7.4; assuming [uric acid](plasma) = 0.3
mM). Among the biological molecules in human plasma whose rates of reaction
with peroxynitrite have been reported, CO, is one of the fastest with a ps
eudo-first-order rate constant k(co2/plasma) = 46 s(-1) (T = 37 degrees C,
pH 7.4; assuming [CO2](plasma) = 1 mM). Thus peroxynitrite reacts with CO2
in human blood plasma nearly 920 times faster than with uric acid. Therefor
e, uric acid does not directly scavenge peroxynitrite because uric acid can
not compete for peroxynitrite with CO,. The therapeutic effects of uric ac
id may be related to the scavenging of the radicals CO3.- and NO; that are
formed from the reaction of peroxynitrite with CO,. We suggest that trappin
g secondary radicals that result from the fast reaction of peroxynitrite wi
th CO, may represent a new and viable approach for ameliorating the adverse
effects associated with peroxynitrite in many diseases. (C) 2000 Academic
Press.