Nonstandard abbreviations used: superoxide anion (O2–); peroxynitrite (ONOO–); peroxynitrous acid (ONOOH); nitrosoperoxycarbonate (ONO2CO2–); nitroxyl anion (NO–); 8-oxo-7, 8-dihydrodeoxyguanosine (8-oxo-dG); 8-oxo-7, 8-dihydrodeoxyadenosine (8-oxo-dA); 5-hydroxydeoxycytidine (5-hydroxy-dC); 2′-deoxyadenosine (dA); 2′-deoxycytidine (dC); 2′-deoxyguanosine (dG); 2′-deoxythymidine (dT); malondialdehyde (MDA); 4-hydroxynonenal (4-HNE); pyrimidopurinone (M1dG); 8-hydroxypropanodeoxyguanosine (HO-PdG); methionine sulfoxide reductase A (MSRA). cage to react with cellular constituents (5). ONOO–reacts with CO2 to form a carbonate adduct, nitrosoperoxycarbonate (ONO2CO2–)(6). The level of CO2 in most tissues is sufficient to trap all of the ONOO–released from inflammatory cells. The carbonate adduct is not as strong an oxidant as ONOO–or ONOOH, but it is an effective nitrating agent. The mechanism of nitration is believed to involve homolytic scission of ONO2CO2–to carbonate radical, which can either oxidize NO2• to NO2+ or oxidize DNA or protein to a derivative that then couples with NO2• to form a nitro derivative (eg, tyrosine→ tyrosyl radical; guanine→ guanyl radical)(7).

In the presence of O2, NO generates a nitrosating agent that reacts with sulfhydryl groups to form S-nitroso derivatives (8). The chemistry of nitrosation is complex, but N2O3 appears to be the principal nitrosating agent produced. S-nitroso derivatives of proteins can demonstrate altered structural and functional properties depending upon their location in the protein. They also can transfer the nitroso group to other thiol-containing molecules (eg, glutathione) or react with thiols to form mixed disulfides and release nitroxyl anion (NO–). H2O2 produced by inflammatory cells oxidizes myeloperoxidase to a higher oxidation state that has a redox potential in excess of 1 V. This higher oxidation state (a ferryl-oxo complex) oxidizes Cl–to HOCl, which is capable of oxidizing or chlorinating cellular macromolecules (Figure 1)(9). HOCl also reacts with amines to form chloramines or with Cl–to form Cl2 gas; the latter chlorinates DNA or protein (10). A similar cascade of reactions is triggered by bromoperoxidase in eosinophils (11). Myeloperoxidase also can oxidize nitrite to NO2•, which can react with NO to form N2O3. This reaction may serve as an alternate pathway of protein nitrosation to the uncatalyzed reaction that produces N2O3 (which requires four NOs and O2)(12).