Toxicity peroxynitrite

Besides cell signaling, superoxide production by nonphagocytic cells may exhibit damaging activity through the interaction with nitric oxide to form peroxynitrite, toxic effects of which were considered in Chapter 21. On the other hand, a decrease in NO concentration may result in endothelial dysfunction due to reduction in endothelium-dependent vasorelaxations... 

There are numerous data that peroxynitrite is involved in cell death and tissue injuries in many clinical conditions. An important mechanism underlying peroxynitrite toxicity is the reaction of tyrosine nitration. Tyrosine nitration inactivates certain enzymes, as was postulated for prostacyclin (PGI2) synthase (M14), cytochrome P450 2B1 (RIO), tyrosine hydroxylase (A 14), and MnSOD (Yl). Moreover, nitration blocks tyrosine phosphorylation, and thus interferes with the tyrosine kinase signaling pathways (K18). The peroxynitrite treatment of rat liver epithelial cells stimulates mitogen-activated protein kinases p38 MAPK, JNK1/2, and ERK1/2 the mechanism of this effect awaits elucidation (S9). 

Complementary to vascular compromise and mechanically impaired axoplasmic flow, additional pathogenic mechanisms (Figures 30.3 30.4) that underlie glaucomatous optic neuropathy include excitotoxic damage from excessive retinal glutamate, peroxynitrite toxicity from increased nitric oxide synthase activity, immune-media ted nerve damage, and oxidative stress (Naskar and Dreyer, 2001). 

Peroxynitrite is able to oxidise methionine residues and to nitrate tyrosine residues in proteins. Nitration of tyrosine residues may contribute significantly to peroxynitrite toxicity, since nitration will prevent the phosphorylation or nucleotidylation of key tyrosine residues in enzymes which are regulated by phosphorylation/ adenylation, thereby seriously compromising one of the most important mechanisms of cellular regulation and signal transduction. 

Imam, S.Z., Ali, S.F. Selenium, an antioxidant, attenuates methamphetamine-induced dopaminergic toxicity and peroxynitrite generation. Brain Res. 855 186, 2000. 

Peroxynitrite, a non-radical product, is formed by the reaction of NO and CV-and is highly toxic to cells. 

Both vitamin E and vitamin C are able to react with peroxynitrite and suppress its toxic effects in biological systems. For example, it has been shown [83] that peroxynitrite efficiently oxidized both mitochondrial and synaptosomal a-tocopherol. Ascorbate protected against peroxynitrite-induced oxidation reactions by the interaction with free radicals formed in these reactions [84]. 

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210 ... 

FIGURE 7.9 (See color insert) Peroxynitrite production by activated macrophages. Cells isolated from control (CTL) and toxicant (TOX)-treated animals were cultured overnight in the presence of IFNa + LPS. Phorbol myristate acetate was then added. Thirty minutes later, the cells were loaded with DHR 123. After 5 minutes incubation, the cells were rinsed and analyzed for fluorescence associated with peroxynitrite production by confocal microscopy. 

Figure I. Reaction of NO with superoxide (02 0form the toxic peroxynitrite (0=N00 ).

Nitric oxide, which is produced from arginine in the reaction catalysed by nitric oxide synthase, reacts with O2 to produce the very toxic peroxynitrite free radical (Figure 17.27). 

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). 

The potentially greater toxicity of peroxynitrite can be readily visualized by comparing the mean diffusion distances that various nitrogen and oxygen-centered species may traverse in one lifetime. The definition of lifetime (t) is the time required for 67% of the initial concentration to decompose, and is readily calculated as the reciprocal of the pseudo-first-order rate constant for the disappearance of the species in question. Distances were calculated from the following equation, which is readily derived from the Fick s laws of diffusion (Nobel, 1983 Pryor, 1992). 

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