Reactive oxygen species peroxynitrite

Sterol carrier protein 2 has also been shown to be involved in the intracellular transport and metabolism of cholesterol. Hirai et al. (1994) suggested that sterol carrier protein 2 plays an important role during foam cell formation induced by acetylated LDL and may be an important step in atherosclerosis [142], Lipoproteins can bind lipopolysaccharide and decrease the lipopoly-saccharide-stimulated production of proinflammatory cytokines [142, 143], In addition, lipoprotein entrapment by the extracellular matrix can lead to the progressive oxidation of LDL because of the action of lipoxygenases, reactive oxygen species, peroxynitrite, or myeloperoxidase [144, 145],... 

Similar to reactive oxygen species, nitric oxide, peroxynitrite, and other nitrogen oxide species produced by mitochondria are able to stimulate or inhibit apoptosis. Proapoptotic effect of nitric oxide was probably first shown by Albina et al. [138], who demonstrated NO-induced... 

Nitric oxide and peroxynitrite contribute to oxidative damage 569 Production of eicosanoids from polyunsaturated fatty acids such as arachidonic acid may generate reactive oxygen species 570 Brain antioxidant defenses modify ischemia-reperfusion injury 570 Reactive oxygen species may modify both the excitotoxic and the apoptotic components of ischemic brain damage 570... 

XOR is a cytoplasmic enzyme and a ready source of electrons for transfer to molecular oxygen to form reactive oxygen species such as superoxide and peroxide. It is therefore thought to be involved in free radical-generated tissue injury and has been implicated in the pathogenesis of ischemia-reperfusion damage. Moreover, it has recently been implicated in the production of peroxynitrite (89), and carbonate radical anion (92), both potent biological oxidants. Its exact role in lipid peroxidation, inflammation, and infection needs... 

Mitochondrial function. NO is able to react with transition metals such as iron, including those contained within haem groups. Even at low NO concentrations there is competition between oxygen and NO for reversible binding to cytochrome c oxidase. If mitochondrial 02 is low respiration slows, which may confer anti-apoptotic benefit to the cell. As NO concentration rises and peroxynitrite is formed, electron transport is irreversibly inhibited, there is increased production of superoxide and other reactive oxygen species and apoptosis occurs. 

A study has been undertaken to clarify whether glucocorticoid excess affects endothelium-dependent vascular relaxation in glucocorticoid treated patients and whether dexamethasone alters the production of hydrogen peroxide and the formation of peroxynitrite, a reactive molecule between nitric oxide and superoxide, in cultured human umbilical endothelial cells (7). Glucocorticoid excess impaired endothelium-dependent vascular relaxation in vivo and enhanced the production of reactive oxygen species to cause increased production of peroxynitrite in vitro. Glucocorticoid-induced reduction in nitric oxide availability may cause vascular endothelial dysfunction, leading to hypertension and atherosclerosis. 

The production of superoxide anions is one of the major factors involved in NO toxicity because superoxide anions can react with NO to form the highly toxic free-radical peroxynitrite. A pivotal role for superoxide anions in NO-related insults is emphasized by results showing that transgenic mice overexpressing superoxide dismutase (SOD) are resistant to brain ischemia. Superoxide can protect against SNP-induced toxicity. Thus, the superoxide-scavenging properties of EGb 761 are likely to explain, at least in part, its ability to block cell death and the increase in reactive oxygen species accumulation induced by the two NO donors used here, SNP and SIN-1. 

Reactive oxygen species such as the hydroxyl radical, superoxide anion, and peroxynitrite are involved in many cellular processes including the inflammatory response. The best known antiinflammatory compound is ebselen (59, R = Ph). It is shown to be a neuroprotective agent and an inhibitor of free radical-induced apoptosis [20, 248, 249], It has undergone phase III clinical trials and is soon to become the first synthetic organoselenium therapeutic released on the market. 

The other amino acid residue present in proteins that is susceptible to oxidation is the indole moiety of tryptophan (Fig. 11). The reducing potential of tryptophan is considerably less than that of cysteine and methionine, so oxidation of tryptophanyl residues usually does not occur until all exposed thiol residues are oxidized. Also, the spontaneous oxidation of tryptophanyl residues in proteins is much less probable than that of cysteinyl and methionyl residues. Tryptophan residues are the only chromophoric moieties in proteins which can be photooxi-dized to tryptophanyl radicals by solar UV radiation, even by wavelengths as long as 305 nm (B12). Tryptophanyl residues readily react with all reactive oxygen species, hypochlorite, peroxynitrite, and chloramines. Oxidative modifications of other amino acid residues require use of strong oxidants, which eventually are produced in the cells. Detailed mechanisms of action of these oxidants is described in subsequent sections of this chapter. 

Figure 11.11. Role of NO in the killing of microbes by macrophages. Microbes are ingested, and peroxisomes fuse to the phagosomes, releasing reactive oxygen species. NO enters the phagosomes and either forms peroxynitrite by reaction with reactive oxygen species, or it diffuses across the microbial cell wall to wreak havoc inside.

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