Peroxynitrite formation

Beckman, J.S. and Crow, J.P. 1993. Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem. Soc. Trans. 21 330-334. 

At present, new developments challenge previous ideas concerning the role of nitric oxide in oxidative processes. The capacity of nitric oxide to oxidize substrates by a one-electron transfer mechanism was supported by the suggestion that its reduction potential is positive and relatively high. However, recent determinations based on the combination of quantum mechanical calculations, cyclic voltammetry, and chemical experiments suggest that °(NO/ NO-) = —0.8 0.2 V [56]. This new value of the NO reduction potential apparently denies the possibility for NO to react as a one-electron oxidant with biomolecules. However, it should be noted that such reactions are described in several studies. Thus, Sharpe and Cooper [57] showed that nitric oxide oxidized ferrocytochrome c to ferricytochrome c to form nitroxyl anion. These authors also proposed that the nitroxyl anion formed subsequently reacted with dioxygen, yielding peroxynitrite. If it is true, then Reactions (24) and (25) may represent a new pathway of peroxynitrite formation in mitochondria without the participation of superoxide. 

Another mode of antioxidant activity of ebselen is the suppression of peroxynitrite formation. Ebselen rapidly reacts with peroxynitrite to form ebselen Se-oxide [332]. Ebselen Se-oxide is reduced by glutathione [333] therefore, ebselen can be regenerated under in vivo conditions by redox cycling (Figure 29.20). 

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

Mutus, B., Redmond, R. W., Akhter, S., Evidence for peroxynitrite formation during S-nitrosoglutathione photolysis in air saturated solutions, FEBS Lett. 449 (1999), p. 79-82... 

Ischiropoulos, H., Zhu, L., and Beckman, J. S., 1992, Peroxynitrite formation from macrophage-derived nitric oxide, Arc/j. Biochem. Biophys. 298 446-451. 

Many pathological conditions, including ischemia/reperfusion, inflammation, and sepsis may induce tissues to simultaneously produce both superoxide and nitric oxide. For example, ischemia allows intracellular calcium to accumulate in endothelium (Fig. 20). If the tissue is reperfused, the readmission of oxygen will allow nitric oxide as well as superoxide to be produced (Beckman, 1990). For each 10-fold increase in the concentration of nitric oxide and superoxide, the rate of peroxynitrite formation will increase by 100-fold. Sepsis causes the induction of a second nitric oxide synthase in many tissues, which can produce a thousand times more nitric oxide than the normal levels of the constitutive enzyme (Moncada et al., 1991). Nitric oxide and indirectly peroxynitrite have been implicated in several important disease states. Blockade of nitric oxide synthesis with N-methyl or N-nitroarginine reduces glutamate-induced neuronal degeneration in primary cortical cultures (Dawson et al., 1991). Nitroarginine also decreases cortical infarct volume by 70% in mice subjected to middle cerebral artery occlusion (Nowicki et al., 1991). Myocardial injury from a combined hy-... 

We have used the nitration of a tyrosine analog with superoxide dismutase to measure the peroxynitrite production from activated rat alveolar macrophages (Fig. 38). The estimated rate of peroxynitrite synthesis was estimated to be 0.1 nmol/10 cells/min (Ischiropoulos et al., 1992a). The rate of nitration was the same whether native Cu,Zn-superoxide dismutase or the phenylglyoxyl-H202 modified superoxide dismutase (which is >99% inhibited with respect to its superoxide scavenging activity) was used (Fig. 39). Three other independent but indirect estimates of peroxynitrite formation were consistent with the superoxide... 

Ischiropoulos, H., Zhu, L., and Beckman, J. S. (1992a). Peroxynitrite formation from activated rat alveolar macrophages. Arch. Biochem. Biophys. 298, 446-451. Ischiropoulos, H., Zhu, L., Chen, J., Tsai, H. M., Martin, J. C., Smith, C. D., and Beckman, J. S. (1992b). Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys. 298, 431-437. 

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... 

I 10 Radi R, Peluffo G, Alvarez MN, et al, Unraveling peroxynitrite formation in biological systems, Free Radic Biol Med 2001 30 463-468. 

Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kan-derian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001 89 E32-E38. 

GSH protection from APAP toxicity. Mitochondrial GSH depletion, peroxynitrite formation, and mitochondrial permeability transition appear to be critical for APAP hepatocellular necrosis. 

H3. Halliwell, B., What nitrates tyrosine Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo FEBS Lett. 411, 157-160 (1997). 

M24. Moriel, R, and Abdalla, D. S., Nitrotyrosine bound to beta-VLDL-apoproteins A biomarker of peroxynitrite formation in experimental atherosclerosis. Biochem. Biophys. Res. Commun. 232, 332-335 (1997). 

To elucidate the mechanisms of NO-induced cellular stress, the effects of SIN-1 (32) on neuroblastoma cells were examined. SIN-1 induced a transient decline in ATP levels and the delayed loss of cell viability, with no significant increase in caspase-3 activity or DNA laddering. NO was suggested to be a potent toxin independent of peroxynitrite formation [41]. 

Jozsef L, Zouki C, Petasis NA, Serhan CN, Eilep JG (2002) Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NE-kappa B and AP-1 activation, and 11, 8 gene expression in human leukocytes. Proc Natl Acad Sci USA 99 13266-13271... 

Huang CC, Chan SH, Hsu KS (2004) 3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. Mol Pharmacol 66 492-501... 

Conditions which favor peroxynitrite formation could result in dramatic shifts in the nitrite/nitrate ratio as well as significant loss of total nitrogen oxides through tyrosine nitration. 

---