Peroxynitrite-induced oxidation

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]. 

Flavonoids exhibit protective action against LDL oxidation. It has been shown [145] that the pretreatment of macrophages and endothelial cells with tea flavonoids such as theaflavin digallate diminished cell-mediated LDL oxidation probably due to the interaction with superoxide and the chelation of iron ions. Quercetin and epicatechin inhibited LDL oxidation catalyzed by mammalian 15-lipoxygenase, and are much more effective antioxidants than ascorbic acid and a-tocopherol [146], Luteolin, rutin, quercetin, and catechin suppressed copper-stimulated LDL oxidation and protected endogenous urate from oxidative degradation [147]. Quercetin was also able to suppress peroxynitrite-induced oxidative modification of LDL [148],... 

Water-soluble organotellurium compounds have been demonshated as protectors against peroxynitrite-induced oxidation in solution. The p-CFj-substituted member is less reactive than the unsubstituted co-partner. ... 

J.C. Niles et al., Peroxynitrite-induced oxidation and nitration products of guanine and 8-oxoguanine Structures and mechanisms of product formation. Nitric Oxide 14, 109-121... 

Chericoni, S., Prieto, J.M., lacopini, P., Cioni, P., and Morelli, 1. 2005. In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes. Journal of Agricultural Food Chemistry, 53 4762-4765. 

Ippoushi, K., Azuma, K., Ito, H., Horie, H., and Higashio, H. 2003. [6]-Gingerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophages prevents peroxynitrite-induced oxidation nitration reactions. Life Sci., 73 3427-3437. 

Yokoyama, A., H. Sakakibara, A. Crozier et al. 2009. Quercetin metabolites and protection against peroxynitrite-induced oxidative hepatic injury in rats. Free Radical Res. 43(10) 913-921. 

Okamoto T, Akaike T, Sawa T et al (2001) Activation of matrix metaUoproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 276 29596-29602... 

Radi, R., Beckman, J.S., Bush, K.M., and Freeman, B.A. 1991. Peroxynitrite-induced membrane lipid peroxidation The cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys., 288 481-7. 

Calcium antagonists are able to affect nitric oxide production and suppress the peroxyni-trite-induced damage. Thus, nifedipine enhanced the bioavailability of endothelial NO in porcine endothelial cell cultures supposedly through an antioxidative mechanism [288], Pretreatment with nisoldipine, a vascular-selective calcium blocker of dihydropyridine-type, of confluent bovine aortic endothelial cells suppressed the peroxynitrite-induced GSH loss and increased cell survival [289]. 

High antioxidative activity carvedilol has been shown in isolated rat heart mitochondria [297] and in the protection against myocardial injury in postischemic rat hearts [281]. Carvedilol also preserved tissue GSL content and diminished peroxynitrite-induced tissue injury in hypercholesterolemic rabbits [298]. Habon et al. [299] showed that carvedilol significantly decreased the ischemia-reperfusion-stimulated free radical formation and lipid peroxidation in rat hearts. Very small I50 values have been obtained for the metabolite of carvedilol SB 211475 in the iron-ascorbate-initiated lipid peroxidation of brain homogenate (0.28 pmol D1), mouse macrophage-stimulated LDL oxidation (0.043 pmol I 1), the hydroxyl-initiated lipid peroxidation of bovine pulmonary artery endothelial cells (0.15 pmol U1), the cell damage measured by LDL release (0.16 pmol l-1), and the promotion of cell survival (0.13 pmol l-1) [300]. SB 211475 also inhibited superoxide production by PMA-stimulated human neutrophils. 

The above examples point out at the direct stimulation of apoptosis by nitric oxide. At the same time, the exclusively rapid reaction of NO with superoxide always suggests the possibility of peroxynitrite participation in this process [141] correspondingly, the role peroxynitrite in the stimulation of apoptosis has been considered. Bonfoco et al. [144] has found that the producers of low peroxynitrite concentrations during the exposure of cortical neurons to the low level of NMDA or the use of peroxynitrite donors resulted in an apoptosis in neurons, while the high concentrations of peroxynitrite induced necrotic cell damage. The formation of peroxynitrite is apparently responsible for NO-stimulated apoptosis in superoxide-generating transformed fibroblasts because nontransformed cells, which do not produce superoxide, were not affected by nitric oxide [145]. It is of interest that proapoptotic effect of peroxynitrite may depend on the cell type. Thus, the formation of peroxynitrite enhanced the NO-induced apoptosis in glomerular endothelial cells, while superoxide inhibited the formation of ceramide and apoptosis in these cells exposed to nitric oxide probably due to peroxynitrite formation... 

Peroxynitrite has been suggested to be formed from nitric oxide and superoxide in vivo. It is a highly reactive oxidant, and causes nitration on the aromatic ring of free tyrosine and protein tyrosine residues. It was reported that peroxynitrite induced various oxidative damage in vitro, for example LDL oxidation, lipid peroxidation, and DNA strand breakage [30]. 

Peroxynitrite, like other oxidants, reacts with proteins, first oxidizing cysteine methionine and tryptophan residues (A7). The reaction products are sulfones, carbonyl moieties, and dityrosines (K23, M29). Formation of protein hydroperoxides and protein fragmentation was also observed (B7, G6). Nitric oxide induces oxidation of methionine residues, thus effecting oxidative damage to proteins (Cl 1). It also reacts with Fe-S clusters of aconitase (D15), though in most cases it is difficult to assess whether these effects are produced by the NO itself, or rather by a more reactive secondary product such as peroxynitrite (C5). At physiological... 

Gow AJ, Duran D, Malcolm S, Ischiropoulos H (1996) Effects of peroxynitrite-induced protein modifications on tyrosine phosphorylation and degradation. FEES Lett 385 63-66 Grune T, Merker K, Sandig G, Davies KJ (2003) Selective degradation of oxidatively modified protein substrates by the proteasome. Biochem Biophys Res Commun 305 709-718 Halliwell B (2002) Hypothesis proteasomal dysfunction a primary event in neurogeneration that leads to nitrative and oxidative stress and subsequent cell death. Ann N Y Acad Sci 962 182-194... 

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