Inhibition of peroxidase-catalyzed reactions by deferoxamine.
Phagocytes generate superoxide (O2-.) and hydrogen peroxide (H2O2) and their interaction in an iron-catalyzed reaction to form hydroxyl radicals (OH.) (Haber-Weiss reaction) has been proposed. Deferoxamine chelates iron in a catalytically inactive form, and thus inhibition by deferoxamine has been employed as evidence for the involvement of OH. generated by the Haber-Weiss reaction. We report here that deferoxamine also inhibits reactions catalyzed by the peroxidases of phagocytes, i.e., myeloperoxidase (MPO) and eosinophil peroxidase (EPO). The reactions inhibited include iodination in the presence and absence of chloride and the oxidation of guaiacol. Iodination by MPO and H2O2 is stimulated by chloride due to the intermediate formation of hypochlorous acid (HOCl). Iodination by reagent HOCl also is inhibited by deferoxamine with the associated consumption of HOCl. Iron saturation of deferoxamine significantly decreased but did not abolish its inhibitory effect on iodination by MPO + H2O2 or HOCl. Deferoxamine did not affect the absorption spectrum of MPO, suggesting that it does not react with or remove the heme iron. The conversion of MPO to Compound II by H2O2 was not seen when H2O2 was added to MPO in the presence of deferoxamine, suggesting either that deferoxamine inhibited the formation of Compound II by acting as an electron donor for MPO Compound I or that deferoxamine immediately reduced the Compound II formed. Iodination by stimulated neutrophils also was inhibited by deferoxamine, suggesting an effect on peroxidase-catalyzed reactions in intact cells. Thus deferoxamine has multiple effects on the formation and activity of phagocyte-derived oxidants and therefore its inhibitory effect on oxidant-dependent damage needs to be interpreted with caution.
Klebanoff
S J
SJ
Department of Medicine, University of Washington, Seattle 98195.
Waltersdorph
A M
AM
D000818:Animals; D002712:Chlorides / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology*; D004285:Dogs; D047209:Eosinophil Peroxidase; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology; D007455:Iodine / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D010544:Peroxidases / Q000037:antagonists & inhibitors; D010586:Phagocytes / Q000201:enzymology*; D013053:Spectrophotometry; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002712:Chlorides; D013481:Superoxides; D006997:Hypochlorous Acid; D007455:Iodine; D006861:Hydrogen Peroxide; D047209:Eosinophil Peroxidase; D010544:Peroxidases; D009195:Peroxidase; D003676:Deferoxamine; D013755:Tetradecanoylphorbol Acetate