NO - Besoin d'assistance

Mechanisms and Biomarkers (WG 4) page 10
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physiological role through AP-1 and the resulting gene transcription (Brennan and O’Neill,
1995).
The Nitric oxide (NO°) is an important free radical as it is involved in the physiology
particularly through the control of regulation of blood tension (Moncada and Higgs, 1993); it
was also defined as endothelium derived relaxing factor (EDRF). NO° can readily react with
superoxide anion leading to the formation of peroxynitrite anion (ONOO-) (Beckman et al.,
1994). The latter reaction occurred at near diffusion controlled limits at approximately 3 times
the dismutation rate of the anion superoxide by the dismutase. Thus, depending on conditions,
each of these radicals can control the action of the others. The resultant peroxynitrite anion
can be an aggressive molecule capable of damaging many biologically active molecules.
However, it has a pKa of 6.8 such that at physiological pH of about 7, a protonation occurred
leading to the formation of peroxynitrous acid (ONOOH). At pH 7.0, this strong oxidant
could be broken by homolytic scission into two radicals, hydroxyl radical and nitronium. The
labile NO° radical with an estimated half-life of around 1 second may have a longer lifespan
in the tissues before reacting with oxygen and water to form nitrites and nitrates. The
determination of these latter compounds is an indicative of the formation of NO°. This latter
is mainly formed from the metabolism of arginine to citrulline by specific enzymes, the nitric
oxide synthases (NOS), existing in different isomer forms which are either constitutive (c-
NOS) such as those found in the endothelial cells (e-NOS) and in the brain or inducible (i-
NOS) in certain conditions such as those found in the immune cells and in the liver (Snyder
and Bredt, 1992).
Oxidants and biological components interactions
The deleterious effects of the reactive oxygen- and nitrogen-species formed in the organism
are expressed through the reactions occurring with the other constitutive biological molecules
i.e. the lipids, the proteins, and the DNA bases.
Lipid oxidation
The main target of free radicals are the polyunsaturated fatty acids of cell membranes
and lipoproteins (Halliwell and Chirico, 1995 ; Rubbo et al., 1994). The major reactive
species involved in lipid peroxidation are hydroxyl radical and peroxynitrite. The mechanism
underlying the reaction is an hydrogen abstraction from a methylene group of unsaturated
fatty acyl chain. The initial lipid radical formed undergoes several fates including a
rearrangement of the double bonds to stabilise the oxidised molecule and that results in
conjugated diene formation and then a decomposition resulting to the formation of alkanals