scholarly journals Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide

1997 ◽  
Vol 321 (2) ◽  
pp. 503-508 ◽  
Author(s):  
Anthony J. KETTLE ◽  
Craig A. GEDYE ◽  
Christine C. WINTERBOURN
Keyword(s):  
Hydrogen Peroxide ◽  
Acid Production ◽  
Hypochlorous Acid ◽  
Potent Inhibitor ◽  
Reduced Glutathione ◽  
Acid Hydrazide ◽  
Inflammatory Cells ◽  
Aminobenzoic Acid ◽  
Irreversible Inhibition ◽  
Enzyme Turnover

Hypochlorous acid is the most powerful oxidant generated by neutrophils and is likely to contribute to the damage mediated by these inflammatory cells. The haem enzyme myeloperoxidase catalyses its production from hydrogen peroxide and chloride. 4-Aminobenzoic acid hydrazide (ABAH) is a potent inhibitor of hypochlorous acid production. In this investigation we show that, in the presence of hydrogen peroxide, ABAH irreversibly inactivates myeloperoxidase. ABAH was oxidized by myeloperoxidase, and kinetic analysis of the inactivation conformed to that for a mechanism-based inhibitor. Inactivation was exacerbated by concentrations of hydrogen peroxide greater than 50 ƁM and by the absence of oxygen. Hydrogen peroxide alone caused minimal inactivation. Reduced glutathione inhibited the oxidation of ABAH as well as the irreversible inhibition of myeloperoxidase. In the presence of oxygen, ABAH and hydrogen peroxide initially converted myeloperoxidase into compound III, which susequently lost haem absorbance. In the absence of oxygen, the enzyme was converted into ferrous myeloperoxidase and its haem groups were rapidly destroyed. We propose that myeloperoxidase oxidizes ABAH to a radical that reduces the enzyme to its ferrous intermediate. Ferrous myeloperoxidase reacts either with oxygen to allow enzyme turnover, or with hydrogen peroxide to give irreversible inactivation.

Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione

2009 ◽  
Vol 425 (1) ◽  
pp. 285-293 ◽  
Author(s):  
Valdecir F. Ximenes ◽  
Ghassan J. Maghzal ◽  
Rufus Turner ◽  
Yoji Kato ◽  
Christine C. Winterbourn ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Nadph Oxidase ◽  
Tissue Damage ◽  
Acid Production ◽  
Hypochlorous Acid ◽  
Human Neutrophils ◽  
Toxic Metabolite ◽  
Inflammatory Processes ◽  
Physiological Substrates ◽  
Inflammatory Tissue

During inflammatory events, neutrophils and platelets interact to release a variety of mediators. Neutrophils generate superoxide and hydrogen peroxide, and also discharge the haem enzyme myeloperoxidase. Among numerous other mediators, platelets liberate serotonin (5-hydroxytryptamine), which is a classical neurotransmitter and vasoactive amine that has significant effects on inflammation and immunity. In the present study, we show that serotonin is a favoured substrate for myeloperoxidase because other physiological substrates for this enzyme, including chloride, did not affect its rate of oxidation. At low micromolar concentrations, serotonin enhanced hypochlorous acid production by both purified myeloperoxidase and neutrophils. At higher concentrations, it almost completely blocked the formation of hypochlorous acid. Serotonin was oxidized to a dimer by myeloperoxidase and hydrogen peroxide. It was also converted into tryptamine-4,5-dione, especially in the presence of superoxide. This toxic quinone was produced by stimulated neutrophils in a reaction that required myeloperoxidase. In plasma, stimulated human neutrophils oxidized serotonin to its dimer using the NADPH oxidase and myeloperoxidase. We propose that myeloperoxidase will oxidize serotonin at sites of inflammation. In doing so, it will impair its physiological functions and generate a toxic metabolite that will exacerbate inflammatory tissue damage. Consequently, oxidation of serotonin by myeloperoxidase may profoundly influence inflammatory processes.

scholarly journals Liposomal Ellagic Acid Alleviates Cyclophosphamide-Induced Toxicity and Eliminates the Systemic Cryptococcus neoformans Infection in Leukopenic Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 882
Author(s):  
Masood Alam Khan ◽  
Arif Khan ◽  
Mohd Azam ◽  
Khaled S. Allemailem ◽  
Faris Alrumaihi ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Renal Function ◽  
Survival Rate ◽  
Cryptococcus Neoformans ◽  
Ellagic Acid ◽  
Histological Analysis ◽  
Reduced Glutathione ◽  
Inflammatory Cells ◽  
Fungal Burden ◽  
Fungal Load

Cryptococcus neoformans infections rose sharply due to rapid increase in the numbers of immunocompromised individuals in recent years. Treatment of Cryptococcosis in immunocompromised persons is largely very challenging and hopeless. Hence, this study aimed to determine the activity of ellagic acid (EA) in the treatment of C. neoformans in cyclophosphamide injected leukopenic mice. A liposomal formulation of ellagic acid (Lip-EA) was prepared and characterized, and its antifungal activity was assessed in comparison to fluconazole (FLZ). The efficacy of the drug treatment was tested by assessing survival rate, fungal burden, and histological analysis in lung tissues. The safety of the drug formulations was tested by investigating hepatic, renal function, and antioxidant levels. The results of the present work demonstrated that Lip-EA, not FLZ, effectively eliminated C. neoformans infection in the leukopenic mice. Mice treated with Lip-EA (40 mg/kg) showed 70% survival rate and highly reduced fungal burden in their lung tissues, whereas the mice treated with FLZ (40 mg/kg) had 20% survival rate and greater fungal load in their lungs. Noteworthy, Lip-EA treatment alleviated cyclophosphamide-induced toxicity and restored hepatic and renal function parameters. Moreover, Lip-EA treatment restored the levels of superoxide dismutase and reduced glutathione and catalase in the lung tissues. The effect of FLZ or EA or Lip-EA against C. neoformans infection was assessed by the histological analysis of lung tissues. Lip-EA effectively reduced influx of inflammatory cells, thickening of alveolar walls, congestion, and hemorrhage. The findings of the present study suggest that Lip-EA may prove to be a promising therapeutic formulation against C. neoformans in immunocompromised persons.

scholarly journals Glutathione Participation in the Prevention of Cardiovascular Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1220
Author(s):  
Deyamira Matuz-Mares ◽  
Héctor Riveros-Rosas ◽  
María Magdalena Vilchis-Landeros ◽  
Héctor Vázquez-Meza
Keyword(s):  
Cardiovascular Diseases ◽  
Superoxide Anion ◽  
Reactive Nitrogen Species ◽  
Hypochlorous Acid ◽  
Reduced Glutathione ◽  
Heart Diseases ◽  
Reactive Species ◽  
Oxygen Species ◽  
Cardiovascular Pathologies

Cardiovascular diseases (CVD) (such as occlusion of the coronary arteries, hypertensive heart diseases and strokes) are diseases that generate thousands of patients with a high mortality rate worldwide. Many of these cardiovascular pathologies, during their development, generate a state of oxidative stress that leads to a deterioration in the patient’s conditions associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Within these reactive species we find superoxide anion (O2•–), hydroxyl radical (•OH), nitric oxide (NO•), as well as other species of non-free radicals such as hydrogen peroxide (H2O2), hypochlorous acid (HClO) and peroxynitrite (ONOO–). A molecule that actively participates in counteracting the oxidizing effect of reactive species is reduced glutathione (GSH), a tripeptide that is present in all tissues and that its synthesis and/or regeneration is very important to be able to respond to the increase in oxidizing agents. In this review, we will address the role of glutathione, its synthesis in both the heart and the liver, and its importance in preventing or reducing deleterious ROS effects in cardiovascular diseases.

Effects of minimally invasive surgery on hypochlorous acid production by neutrophils

1994 ◽  
Vol 81 (4) ◽  
pp. 557-560 ◽  
Author(s):  
P. D. Carey ◽  
C. H. Wakefield ◽  
A. Thayeb ◽  
J. R. T. Monson ◽  
A. Darzi ◽  
...  
Keyword(s):  
Minimally Invasive Surgery ◽  
Minimally Invasive ◽  
Invasive Surgery ◽  
Acid Production ◽  
Hypochlorous Acid

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.

scholarly journals Experience of measuring glutathione peroxidase activity in surgically induced endometrial-like lesions in rats

2021 ◽  
Vol 70 (2) ◽  
pp. 55-61
Author(s):  
Aleksey V. Razygraev ◽  
Elena V. Baziyan ◽  
Lyudmila S. Polyanskikh ◽  
Mariya A. Petrosyan
Keyword(s):  
Hydrogen Peroxide ◽  
Antioxidant Enzymes ◽  
Glutathione Peroxidase ◽  
Rat Model ◽  
Peroxidase Activity ◽  
Specific Activity ◽  
Reduced Glutathione ◽  
Glutathione Peroxidase Activity ◽  
Nitrobenzoic Acid ◽  
Surgically Induced

BACKGROUND: Endometriosis is known to be linked with altered activities of antioxidant enzymes and with their gene polymorphisms. Progestins are known to induce glutathione peroxidase activity in the endometrium and promote reduction of endometrial lesions. It could be useful to estimate the correlation between the activity of glutathione peroxidase within endometrial lesions and their degree of reduction. AIM: The present study was aimed at estimating glutathione peroxidase activity in surgically induced endometrial-like lesions of different degree of reduction in rat model of endometriosis. MATERIALS AND METHODS: The method for determining glutathione peroxidase activity using hydrogen peroxide as a substrate and 5,5-dithiobis(2-nitrobenzoic acid) for estimation of residual reduced glutathione was applied for quantitative analysis of the enzyme activity in endometriotic foci, surgically induced in female Wistar rats. An assay of glutathione peroxidase activity in tissue homogenates was performed at 37C in a reaction medium containing Tris-HCl buffer supplemented with tetrasodium ethylenediaminetetraacetate and sodium azide (pH 8.5) in the presence of 0.55 mM reduced glutathione and 0.192 mM hydrogen peroxide. Before adding trichloroacetic acid, 40-second incubation was used. The correlation between the specific activity of the enzyme and protein amount in endometriotic foci was estimated. RESULTS: In a rat model of endometriosis, there was a high, well-determined glutathione peroxidase activity in endometriotic foci. For the same endometriotic tissue sample, the enzymatic activity was proportional to the amount of protein in the reaction mixture. The range of specific glutathione peroxidase activity was 2.436.45 micromoles of consumed glutathione per minute per milligram of protein (n = 7). In most reduced endometriotic foci (with the minimum amount of endometriotic tissue), the highest specific activity of glutathione peroxidase was found (the Spearmans rho of 0.93 with p = 0.0067). CONCLUSIONS: The method for determining glutathione peroxidase activity using hydrogen peroxide and 5,5-dithiobis(2-nitrobenzoic acid) is convenient for working with the endometriotic tissue in a rat model of endometriosis. We can accept, with p 0.01, that weight of endometriotic foci is negatively linked with specific glutathione peroxidase activity within their tissue. The results are analogous to the previously obtained data on catalase activity and suggest the involvement of both antioxidant enzymes in reduction of endometrial lesions.

scholarly journals Myeloperoxidase Modulates Hydrogen Peroxide Mediated Cellular Damage in Murine Macrophages

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1255
Author(s):  
Chaorui Guo ◽  
Inga Sileikaite ◽  
Michael J. Davies ◽  
Clare L. Hawkins
Keyword(s):  
Hydrogen Peroxide ◽  
Hypochlorous Acid ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Cellular Damage ◽  
Enzymatic System ◽  
Therapeutic Approaches ◽  
Macrophage Cell

Myeloperoxidase (MPO) is involved in the development of many chronic inflammatory diseases, in addition to its key role in innate immune defenses. This is attributed to the excessive production of hypochlorous acid (HOCl) by MPO at inflammatory sites, which causes tissue damage. This has sparked wide interest in the development of therapeutic approaches to prevent HOCl-induced cellular damage including supplementation with thiocyanate (SCN−) as an alternative substrate for MPO. In this study, we used an enzymatic system composed of glucose oxidase (GO), glucose, and MPO in the absence and presence of SCN−, to investigate the effects of generating a continuous flux of oxidants on macrophage cell function. Our studies show the generation of hydrogen peroxide (H2O2) by glucose and GO results in a dose- and time-dependent decrease in metabolic activity and cell viability, and the activation of stress-related signaling pathways. Interestingly, these damaging effects were attenuated by the addition of MPO to form HOCl. Supplementation with SCN−, which favors the formation of hypothiocyanous acid, could reverse this effect. Addition of MPO also resulted in upregulation of the antioxidant gene, NAD(P)H:quinone acceptor oxidoreductase 1. This study provides new insights into the role of MPO in the modulation of macrophage function, which may be relevant to inflammatory pathologies.

scholarly journals Hypochlorous acid is a potent inhibitor of GST P1-1

2001 ◽  
Vol 138 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Rachel I.M van Haaften ◽  
Gertjan J.M den Hartog ◽  
Chris T.A Evelo ◽  
Guido R.M.M Haenen ◽  
Aalt Bast
Keyword(s):  
Hypochlorous Acid ◽  
Potent Inhibitor
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