scholarly journals Superoxide modulates the activity of myeloperoxidase and optimizes the production of hypochlorous acid

1988 ◽  
Vol 252 (2) ◽  
pp. 529-536 ◽  
Author(s):  
A J Kettle ◽  
C C Winterbourn
Keyword(s):  
Superoxide Dismutase ◽  
Xanthine Oxidase ◽  
Hypochlorous Acid ◽  
Direct Reaction ◽  
Chlorination Reaction ◽  
Inactive Compound ◽  
Physiological Conditions ◽  
Oxidant Damage ◽  
Form Compound ◽  
Compound Ii

Myeloperoxidase catalyses the conversion of H2O2 and Cl- to hypochlorous acid (HOCl). It also reacts with O2- to form the oxy adduct (compound III). To determine how O2- affects the formation of HOCl, chlorination of monochlorodimedon by myeloperoxidase was investigated using xanthine oxidase and hypoxanthine as a source of O2- and H2O2. Myeloperoxidase was mostly converted to compound III, and H2O2 was essential for chlorination. At pH 5.4, superoxide dismutase (SOD) enhanced chlorination and prevented formation of compound III. However, at pH 7.8, SOD inhibited chlorination and promoted formation of the ferrous peroxide adduct (compound II) instead of compound III. We present spectral evidence for a direct reaction between compound III and H2O2 to form compound II, and for the reduction of compound II by O2- to regenerate native myeloperoxidase. These reactions enable compound III and compound II to participate in the chlorination reaction. Myeloperoxidase catalytically inhibited O2- –dependent reduction of Nitro Blue Tetrazolium. This inhibition is explained by myeloperoxidase undergoing a cycle of reactions with O2-, H2O2 and O2-, with compounds III and II as intermediates, i.e., by myeloperoxidase acting as a combined SOD/catalase enzyme. By preventing the accumulation of inactive compound II, O2- enhances the activity of myeloperoxidase. We propose that, under physiological conditions, this optimizes the production of HOCl and may potentiate oxidant damage by stimulated neutrophils.

scholarly journals Superoxide dismutase-inhibitible reduction of cytochrome c by the alloxan radical. Implications for alloxan cytotoxicity

1982 ◽  
Vol 207 (3) ◽  
pp. 609-612 ◽  
Author(s):  
C C Winterbourn
Keyword(s):  
Superoxide Dismutase ◽  
Cytochrome C ◽  
Xanthine Oxidase ◽  
Reduced Glutathione ◽  
Direct Reaction ◽  
Cytochrome C Reduction

Cytochrome c was reduced when superoxide was generated from xanthine oxidase in the presence of alloxan, and by the reaction of alloxan and with reduced glutathione. In each case, most of the reduction was inhibited by superoxide dismutase, but considerably more enzyme was required than with superoxide alone. This indicates that the superoxide dismutase-inhibitible cytochrome c reduction was mainly due to a direct reaction with the alloxan radical, and implies that other reactions that are inhibited by superoxide dismutase could be due to either alloxan radicals or superoxide.

scholarly journals Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

2009 ◽  
Vol 421 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Martin D. Rees ◽  
Steven E. Bottle ◽  
Kathryn E. Fairfull-Smith ◽  
Ernst Malle ◽  
John M. Whitelock ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Oxidative Damage ◽  
Hypochlorous Acid ◽  
Inflammatory Diseases ◽  
Antioxidant Compounds ◽  
Protective Effects ◽  
Compound I ◽  
Chloride System ◽  
Ic50 Values ◽  
Compound Ii

Tissue damage resulting from the extracellular production of HOCl (hypochlorous acid) by the MPO (myeloperoxidase)-hydrogen peroxide-chloride system of activated phagocytes is implicated as a key event in the progression of a number of human inflammatory diseases. Consequently, there is considerable interest in the development of therapeutically useful MPO inhibitors. Nitroxides are well established antioxidant compounds of low toxicity that can attenuate oxidative damage in animal models of inflammatory disease. They are believed to exert protective effects principally by acting as superoxide dismutase mimetics or radical scavengers. However, we show here that nitroxides can also potently inhibit MPO-mediated HOCl production, with the nitroxide 4-aminoTEMPO inhibiting HOCl production by MPO and by neutrophils with IC50 values of approx. 1 and 6 μM respectively. Structure–activity relationships were determined for a range of aliphatic and aromatic nitroxides, and inhibition of oxidative damage to two biologically-important protein targets (albumin and perlecan) are demonstrated. Inhibition was shown to involve one-electron oxidation of the nitroxides by the compound I form of MPO and accumulation of compound II. Haem destruction was also observed with some nitroxides. Inhibition of neutrophil HOCl production by nitroxides was antagonized by neutrophil-derived superoxide, with this attributed to superoxide-mediated reduction of compound II. This effect was marginal with 4-aminoTEMPO, probably due to the efficient superoxide dismutase-mimetic activity of this nitroxide. Overall, these data indicate that nitroxides have considerable promise as therapeutic agents for the inhibition of MPO-mediated damage in inflammatory diseases.

scholarly journals Production of the superoxide adduct of myeloperoxidase (compound III) by stimulated human neutrophils and its reactivity with hydrogen peroxide and chloride

1985 ◽  
Vol 228 (3) ◽  
pp. 583-592 ◽  
Author(s):  
C C Winterbourn ◽  
R C Garcia ◽  
A W Segal
Keyword(s):  
Hydrogen Peroxide ◽  
Superoxide Dismutase ◽  
Phorbol Myristate Acetate ◽  
Catalase Activity ◽  
Human Neutrophils ◽  
H2o2 Concentration ◽  
Myristate Acetate ◽  
Similar Product ◽  
Form Compound ◽  
Compound Ii

Examination of the spectra of phagocytosing neutrophils and of myeloperoxidase present in the medium of neutrophils stimulated with phorbol myristate acetate has shown that superoxide generated by the cells converts both intravacuolar and exogenous myeloperoxidase into the superoxo-ferric or oxyferrous form (compound III or MPO2). A similar product was observed with myeloperoxidase in the presence of hypoxanthine, xanthine oxidase and Cl-. Both transformations were inhibited by superoxide dismutase. Thus it appears that myeloperoxidase in the neutrophil must function predominantly as this superoxide derivative. MPO2 autoxidized slowly (t 1/2 = 12 min at 25 degrees C) to the ferric enzyme. It did not react directly with H2O2 or Cl-, but did react with compound II (MP2+ X H2O2). MPO2 catalysed hypochlorite formation from H2O2 and Cl- at approximately the same rate as the ferric enzyme, and both reactions showed the same H2O2-dependence. This suggests that MPO2 can enter the main peroxidation pathway, possibly via its reaction with compound II. Both ferric myeloperoxidase and MPO2 showed catalase activity, in the presence or absence of Cl-, which predominated over chlorination at H2O2 concentrations above 200 microM. Thus, although the reaction of neutrophil myeloperoxidase with superoxide does not appear to impair its chlorinating ability, the H2O2 concentration in its environment will determine whether the enzyme acts primarily as a catalase or peroxidase.

Superoxide, Xanthine Oxidase and Platelet Reactions: Further Studies on Mechanisms by which Oxidants Influence Platelets

1981 ◽  
Vol 45 (03) ◽  
pp. 290-293 ◽  
Author(s):  
Peter H Levine ◽  
Danielle G Sladdin ◽  
Norman I Krinsky
Keyword(s):  
Superoxide Dismutase ◽  
Cytochrome C ◽  
Xanthine Oxidase ◽  
Direct Effect ◽  
Platelet Function ◽  
Experimental Conditions ◽  
Release Reaction

SummaryIn the course of studying the effects on platelets of the oxidant species superoxide (O- 2), Of was generated by the interaction of xanthine oxidase plus xanthine. Surprisingly, gel-filtered platelets, when exposed to xanthine oxidase in the absence of xanthine substrate, were found to generate superoxide (O- 2), as determined by the reduction of added cytochrome c and by the inhibition of this reduction in the presence of superoxide dismutase.In addition to generating Of, the xanthine oxidase-treated platelets display both aggregation and evidence of the release reaction. This xanthine oxidase induced aggreagtion is not inhibited by the addition of either superoxide dismutase or cytochrome c, suggesting that it is due to either a further metabolite of O- 2, or that O- 2 itself exerts no important direct effect on platelet function under these experimental conditions. The ability of Of to modulate platelet reactions in vivo or in vitro remains in doubt, and xanthine oxidase is an unsuitable source of O- 2 in platelet studies because of its own effects on platelets.

Effects of Greek legume plant extracts on xanthine oxidase, catalase and superoxide dismutase activities

2011 ◽  
Vol 68 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Chrysoula I. Spanou ◽  
Aristidis S. Veskoukis ◽  
Dimitrios Stagos ◽  
Kalliopi Liadaki ◽  
Nectarios Aligiannis ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Xanthine Oxidase ◽  
Plant Extracts ◽  
Legume Plant

Flavonoid-induced conversion of catalase to its inactive form—Compound II

2014 ◽  
Vol 48 (11) ◽  
pp. 1334-1341 ◽  
Author(s):  
J. Krych ◽  
J. L. Gebicki ◽  
L. Gebicka
Keyword(s):  
Inactive Form ◽  
Form Compound ◽  
Compound Ii

Hypothalamic superoxide dismutase, xanthine oxidase, nitric oxide, and malondialdehyde in rats fed with fish ω-3 fatty acids

2004 ◽  
Vol 28 (4) ◽  
pp. 693-698 ◽  
Author(s):  
Ahmet Songur ◽  
Mustafa Sarsilmaz ◽  
Sadik Sogut ◽  
Birsen Ozyurt ◽  
Huseyin Ozyurt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fatty Acids ◽  
Superoxide Dismutase ◽  
Xanthine Oxidase

Hyperoxia and self- or neutrophil-generated O2 metabolites inactivate xanthine oxidase

1988 ◽  
Vol 65 (5) ◽  
pp. 2349-2353 ◽  
Author(s):  
L. S. Terada ◽  
C. J. Beehler ◽  
A. Banerjee ◽  
J. M. Brown ◽  
M. A. Grosso ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Xanthine Oxidase ◽  
Superoxide Anion ◽  
Hypochlorous Acid ◽  
Control Mechanism ◽  
Xanthine Dehydrogenase ◽  
Biological Processes ◽  
Lung Endothelial Cells ◽  
Cellular Control

Xanthine oxidase (XO) and xanthine dehydrogenase (XD) activities decreased in lungs isolated from rats and cultured lung endothelial cells that had been exposed to hyperoxia. Purified XO activity also decreased after addition of a variety of chemically generated O2 metabolite species (superoxide anion, hydrogen peroxide, hydroxyl radical, or hypochlorous acid), hypoxanthine, or stimulated neutrophils in vitro. XO inactivation by chemically, self-, or neutrophil-generated O2 metabolites was decreased by simultaneous addition of various O2 metabolite scavengers but not their inactive analogues. Since XO appears to contribute to a variety of biological processes and diseases, hyperoxia- or O2 metabolite-mediated decreases in XO activity may be an important cellular control mechanism.

Allopurinol does not enhance antioxidant properties of extracellular fluid

1988 ◽  
Vol 255 (1) ◽  
pp. H202-H206 ◽  
Author(s):  
B. J. Zimmerman ◽  
D. A. Parks ◽  
M. B. Grisham ◽  
D. N. Granger
Keyword(s):  
Free Radical ◽  
Xanthine Oxidase ◽  
Hypochlorous Acid ◽  
Ischemia Reperfusion ◽  
Parenchymal Cell ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Extracellular Fluid ◽  
Free Radical Scavenging ◽  
Beneficial Effects

Allopurinol has been shown to provide significant protection against ischemia/reperfusion-induced microvascular and parenchymal cell injury. It has been hypothesized that the protection seen with allopurinol after ischemia/reperfusion (I/R) is caused by inhibition of xanthine oxidase. However, recent reports suggest that the beneficial effects of allopurinol in I/R may be caused by direct free radical scavenging. The objective of this study was to determine whether the regimen of allopurinol administration used in most I/R studies leads to a significant modification of the free radical scavenging properties of extracellular fluid (ECF), i.e., plasma and lymph. Plasma and intestinal lymph samples obtained from both control and allopurinol-treated cats were used to assess the following: 1) allopurinol and oxypurinol concentrations, 2) xanthine oxidase inhibition, 3) myoglobin-catalyzed linolenic acid peroxidation, 4) hypochlorous acid scavenging, and 5) protein and nonprotein sulfhydryl content. ECF from allopurinol-treated animals contained approximately 10 microM each of allopurinol and oxypurinol. Ten percent ECF resulted in 80% inhibition of xanthine oxidase activity. Comparable volumes of control ECF did not inhibit xanthine oxidase. Furthermore, allopurinol treatment did not enhance the antioxidant properties of ECF. The results of this study do not support the contention that the beneficial effects of allopurinol in I/R injury are caused by the scavenging of oxidants produced in ECF by activated granulocytes.

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