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(Knowles, McWeeny et al. 1974) and within neutrophil phagocytes with a pH 3.0-6.5 (Cech
and Lehrer 1984). This makes the production of this acid possible in high inflammatory
conditions and after dietary intake of certain nutriments such as smoked and cured foods.
High levels of both NO and NOz during inflammation in the presence of the inducible
nitrogen synthase enzyme (see below) forms dinitrogen trioxde (NzOs). Both NOz- and NOt-
are moderately stable and can be released on tissue contact (Moro, Darley-Usmar et al. t994;
White, Moellering et al. 1997). NO can undergo electron oxidation and reduction reactions
generating nitrosonium cation (NO+) and nitroxyl anion (NO-) and these can participate in
numerous other redox reactions. NO can also regulate apoptotic signals through formation of
reactive NO species (Tamir, Irwis et al. 1993; Kim, Talanian et al. 1997; Nakano, Terato et
aI.2003).
Perioxynitrite anion (ONOO) and peroxynitrous acid (ONOOII) are oxidants which can also
react with numerous targets. The formation requires NO and Oz- anion produced by many cell
types - neutrophils, macrophages, smooth muscle cells endothelial cells and fibroblasts
(Ischiropoulos, Zhu et al. 1992; Kooy and Royall 1994; Boota, Zar et al. 1996; Thom, Xu et
al. 1997). They interact with glucose, fructose, and mannitol (White, Moellering et al. 1997;
Skinner, White et al. 1998), and DNA bases. They hydroxylate aromatic amino acids (such as
tyrosine, tryptophan, phenylalanine), and oxidise thiols and lipids @eckman, Ischiropoulos et
al. t992; Alvarez, Rubbo et al. 1996; Beckman 1996). Perioxynitrite can directly inhibit
oxidation reactions by chain terminating lipid peroxyl and alkoxyl radicals or through
regulation of cell signalling pathways that lead to induction of antioxidant enzymes (@ubbo,
Radi et al. L994; ODonnell, Chumley et al. 1997; Moellering, McAndrew et al. 1998). It can
nitrate both free and protein bound tyrosine residues to give a 3-nitrotyrosine compound
found in high levels in many inflammatory conditions (see below) (van der Vliet, O'Neill et
al. 1994; Alvarez, Rubbo et al. 1996). Addition of ONOO to red blood cells results in
methaemoglobin formation. ONOO also reacts with iron-sulphur enzymes and can lead to
inactivation (Castro, Rodriguez et al. 1994; Bouton, Hirling et al. 1997).
While responsible for many toxic reactions - it is possible that this also provides a mechanism
for removal as the ONOO compound isomerises into NOs- and NOz- at neutral pH (Irwis,
Tamir et al. 1995; Munzel, Sayegh et al. 1995; Pfeiffer, Gorren et al. 1997). It is also possible
that the ONOO- reaction with COz which then degrades which may also be a protective
mechanism (Lymar and Hurst 1996; Uppu and Pryor 1996).
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