Peroxynitrites

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... 

Not all oxidants formed biolc cally have the potential to promote lipid peroxidation. The free radicals superoxide and nitric oxide [or endothelium-derived relaxing aor (EDRF)] are known to be formed in ww but are not able to initiate the peroxidation of lipids (Moncada et tU., 1991). The protonated form of the superoxide radical, the hydroperoxy radical, is capable of initiating lipid peroxidation but its low pili of 4.5 effectively precludes a major contribution under most physiological conditions, although this has been suggested (Aikens and Dix, 1991). Interestingly, the reaction product between nitric oxide and superoxide forms the powerful oxidant peroxynitrite (Equation 2.6) at a rate that is essentially difiiision controlled (Beckman eta/., 1990 Huie and Padmaja, 1993). 

Graham, A., Hogg, N., Kalyanaraman, B., O Leary, V.J., Darley-Usmar, V. and Moncada, S. (1993). Peroxynitrite modification of low density lipoprotein leads to recognition by the macrophage scavenger receptor. FEBS Lett. 330, 181-185. 

Van Der Vliet, A., Smith, D., O Neill, C.A., Kaur, H., Darley-Usmar, V.M., Cross, C.E. and Halliwell, B. (1994). Interactions of peroxynitrite with human plasma and its constituents oxidative damage and antioxidant depletion. Biochem. J. 303, 295-301. 

Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. and Freeman, B.A. (1990). Apparent hydroxyl radical production by peroxynitrite implication for endothelial injury from nitric oxide and superoxide. Proc. Natl Acad. Sci. USA 87, 1620-1624. 

During ischaemia, NOS is activated by calcium influx or by cytokines like tumour necrosis factor (TNF) or by lipopolysaccharide (LPS) and NO is produced in excess. It has been proposed that the excitotoxic effect of glutamate, which contributes to ischaemia-induced neuronal damage, is mediated by increased production of NO via a chain of events that includes increases in intracellular calcium (via glutamate activation of NMDA receptors), calcium activation of NOS, production of NO and peroxynitrite, and induction of lipid peroxidation. In fact, N-nitro-L-atginine, a selective inhibitor of NOS, has been shown to prevent glutamate-induced neurotoxicity in cortical cell cultures (Dawson rf /., 1991). 

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