Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional mechanism of nitric oxide-dependent toxicity.
Involvement of peroxynitrite (ONOO-) in inflammatory diseases has been implicated by detection of 3-nitrotyrosine, an allegedly characteristic protein oxidation product, in various inflamed tissues. We show here that nitrite (NO2-), the primary metabolic end product of nitric oxide (NO.), can be oxidized by the heme peroxidases horseradish peroxidase, myeloperoxidase (MPO), and lactoperoxidase (LPO), in the presence of hydrogen peroxide (H2O2), to most likely form NO.2, which can also contribute to tyrosine nitration during inflammatory processes. Phenolic nitration by MPO-catalyzed NO2- oxidation is only partially inhibited by chloride (Cl-), the presumed major physiological substrate for MPO. In fact, low concentrations of NO2- (2-10 microM) catalyze MPO-mediated oxidation of Cl-, indicated by increased chlorination of monochlorodimedon or 4-hydroxyphenylacetic acid, most likely via reduction of MPO compound II. Peroxidase-catalyzed oxidation of NO2-, as indicated by phenolic nitration, was also observed in the presence of thiocyanate (SCN-), an alternative physiological substrate for mammalian peroxidases. Collectively, our results suggest that NO2-, at physiological or pathological levels, is a substrate for the mammalian peroxidases MPO and lactoperoxidase and that formation of NO2. via peroxidase-catalyzed oxidation of NO2- may provide an additional pathway contributing to cytotoxicity or host defense associated with increased NO. production.
van der Vliet
A
A
Division of Pulmonary/Critical Care Medicine, Department of Internal Medicine, University of California, Davis, California 95616, USA. avandervliet@ucdavis.edu
Eiserich
J P
JP
Halliwell
B
B
Cross
C E
CE
D002384:Catalysis; D005609:Free Radicals; D009566:Nitrates / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*
D005609:Free Radicals; D009566:Nitrates; D009573:Nitrites; C039642:peroxynitric acid; D009569:Nitric Oxide; D009195:Peroxidase