Oxidant peroxynitrite ONOO

The stable free radical nitric oxide (NO) has an important role as a biological messenger. The reaction of NO with superoxide (O2 ) forms the powerful oxidant peroxynitrite (ONOO ), and a mechanism for the reaction of ONOO resulting in the abstraction of H from C—H bonds is shown (equations 109, 110). The formation of HO from the spontaneous decomposition of peroxynitrite, and of COJ radicals from CO2 catalyzed decomposition of peroxynitrite, have been demonstrated. ... 

Chronic inflammatory states associated with infection or xenobiotic chemical exposure from the environment can produce genomic lesions that, in time, can become initiated tumors. It is known that hosts do fight microbial infections by moderate production of various free radicals reactive oxygen species (ROS) [e.g., hydroxyl radical (OH ) and the superoxide radical (OT)] or reactive nitrogen species (RNS) [e.g., nitric oxide (NO ) and the strong oxidant, peroxynitrite (ONOO )]. Within limits inflammatory signaling pathways of the host can control excessive free radical concentrations by means of enzymes such as NADPH oxidase, myeloperoxidase, nitric oxide synthase, and others (Federico et al. 2007 Rakoff-Nahonm 2006). 

NO can interact with other free radicals most notably, NO reacts with the superoxide anion (O 2) to produce the potent oxidant peroxynitrite (ONOO") (Radi et al., 1991). Although it is a simple molecule, ONOO is chemically complex. It can display hydroxyl radical-like and nitrogen dioxide (NO2) radical-like activity, can oxidize lipids, and can directly nitrate proteins. ONOO" has been shown to nitrate a tyrosine residue on superoxide dismutase (SOD) (Beckman et al., 1992). 

A related oxidative hypothesis implicates the molecules nitric oxide, superoxide, and peroxynitrite in the modification of proteins in cells 24, 25). Nitric oxide (NO), produced by intemeurons surrounding motor nuclei, reacts with superoxide (Oi ) approximately three times faster than superoxide does with native SODl, to form the strong oxidant peroxynitrite (ONOO ). It has been proposed that peroxynitrite can react with SODl to form a nitronium-like intermediate wldch can in turn nitrate tyrosine residues (reactions 3 and 4). 

Peroxynitrite (ONOO-) is a cytotoxic reactive species that is formed by the reaction of nitric oxide and superoxide. Methods for measuring the scavenging capacity of peroxynitrite usually depend on either the inhibition of tyrosine nitration or the inhibition of dihydrorhodamine 123 (DHR) oxidation to rhodamine 123 (MacDonalds-Wicks and... 

NO may react with superoxide to yield the highly reactive peroxynitrite, ONOO-. Superoxide may also be converted into H202 and the reactive hydroxyl radical, OH. In this way excessive activation of glutamate receptors leads to oxidative damage. The calcium influx has a major effect on mitochondria and causes them to depolarize and swell. This leads to a pore being formed in the outer mitochondrial membrane, which allows the escape of cytochrome c and procaspases from the mitochondria into the cytosol. Cytochrome c activates the caspase cascade, which leads to apoptotic cell death (Ch. 35). 

Pro-oxidant effects. The antioxidant effect described above occurs when NO concentrations are low. If the concentration of NO rises, rather than reducing the damaging effects of 02" the two may combine to form an even more powerful oxidant called peroxynitrite (ONOO ) ... 

Peroxynitrite (ONOO ) is a cytoxic species that is considered to form nitric oxide (NO) and superoxide (Oj ) in biological systems (Beckman et al. 1990). The toxicity of this compound is attributed to its ability to oxidize, nitrate, and hydroxylate biomolecules. Tyrosine is nitrated to form 3-nitrotyrosine (Ramazanian et al. 1996). Phenylalanine is hydroxylated to yield o-, m-, and p-tyrosines. Cysteine is oxidized to give cystine (Radi et al. 1991a). Glutathione is converted to S-nitro- or S-nitroso derivatives (Balazy et al. 1998). Catecholamines are oxidatively polymerized to melanin (Daveu et al. 1997). Lipids are also oxidized (Radi 1991b) and DNA can be scissored by peroxynitrite (Szabo and Ohshima 1997). 

Deleterious protein cross-linking can also be induced by reactive nitrogen species (RNS) such as peroxynitrite ONOO formed by the reaction of superoxide with nitric oxide (NO). The cross-links are formed between tyrosine residues following nitration by peroxynitrite (Sitte, 2003). Carnosine appears to play roles not only in NO generation but also in protection against excess NO production by inducible nitric oxide synthetase (NOS), thereby preventing ONOO-mediated protein modification (Fontana et ah, 2002). Evidence for a carnosine-NO adduct has also been published (Nicoletti et al., 2007). 

Superoxide (02 ) is the one electron reduced form of molecular oxygen. It reacts irreversibly and at close to the diffusion limit with nitric oxide (Huie and Padmaja, 1993) to form the powerful oxidant peroxynitrite anion (ONOO ). 

Measurement of nitric oxide by absorption into hydrophobic tubing. The apparent disappearance of nitric oxide is due to uptake into the hydrophobic tubing and is independent of the oxygen concentration in the solution. Peroxynitrite (ONOO") rapidly destroys nitric oxide as shown by the rapid decrease in the signal. The details of the basic apparatus are shown in Fig. 18. 

NO reacts very efficiently with superoxide to form peroxynitrite (ONOO-), a highly reactive oxidant that leads to DNA damage, nitration of tyrosine, and oxidation of cysteine to disulfides or to various sulfur oxides (SOx). Several cellular... 

Among the oxygen-derived free radicals, the species of primary concern include superoxide anion (O -), hydrogen peroxide (H202), and hydroxyl radical (OH-). The superoxide is further converted in peroxynitrite (ONOO-) by reacting with nitric oxide. 

Fig. 9.2 Schematic diagram depicting the possible mechanisms by which hyperglycemia/diabetes decreases the expression of Gia proteins and adenylyl cyclase signaling. Diabetes/hyperglycemia augments the levels of vasoactive peptides including Ang II/ET-1 that enhance the oxidative stress by increasing the levels of superoxide anion (O2 ) and peroxynitrite (ONOO ). O2 and ONOO-decrease the levels of Gi proteins.The treatment with antioxidants and ONOO- scavengers reverses the hyperglycemia-induced decreased expression of Gia proteins and adenylyl cyclase signaling.

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