Interaction of myeloperoxidase with diclofenac

Zuurbier, Karin W.M.; Bakkenist, A.R.J.; Fokkens, R.H.; Nibbering, Nico M. M.; Wever, Ron; Muijsers, Anton O.

doi:10.1016/0006-2952(90)90359-s

Cited by 40 publications

(7 citation statements)

References 34 publications

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“…But these values are considerably less than the rate constants which were obtained by our presteady-state stopped-flow measurements [(9.6 ( 0.5) × 10 6 M -1 s -1 at pH 7.0 and 15 °C]. The reason for this discrepancy is the known fact that MPO activity decreases rapidly during the first seconds (29) with the consequence of grossly underestimating the real activity in classical steady-state experiments compared with that in the first milliseconds. Similarly, the values of k Cl -reported in the literature are considerably less than the rate constant obtained by our presteady-state measurements [(2.5 ( 0.3) × 10 4 M -1 s -1 at pH 7.0 and 15 °C].…”

Section: Discussioncontrasting

confidence: 70%

Reaction of Myeloperoxidase Compound I with Chloride, Bromide, Iodide, and Thiocyanate

1998

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Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids. This study for the first time presents transient kinetic measurements of the oxidation of these halides and thiocyanate by the myeloperoxidase intermediate compound I, using the sequential mixing stopped-flow technique. At pH 7 and 15 degrees C, the two-electron reduction of compound I to the native enzyme by Cl- has a second-order rate constant of (2.5 +/- 0.3) x 10(4) M(-1) s(-1), whereas reduction of compound I by SCN- has a second-order rate constant of (9.6 +/- 0.5) x 10(6) M(-1) s(-1). Iodide [(7.2 +/- 0.7) x 10(6) M(-1) s(-1)] is shown to be a better electron donor for compound I than Br- [(1.1 +/- 0.1) x 10(6) M(-1) s(-1)]. The pH dependence studies suggest that compound I reduction by (pseudo-)halides is controlled by a residue with a pKa of about 4.6. The protonation of this group is necessary for optimum (pseudo-)halide anion oxidation. These transient kinetic results are underlined by steady-state spectral and kinetic investigations. SCN- is shown to be most effective in shifting the system myeloperoxidase/hydrogen peroxide from the peroxidatic cycle to the halogenation cycle, whereas iodide is shown to be more effective than bromide which in turn is much more effective than chloride. Decreasing pH increases the rate of this transition. Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity.

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Section: Discussioncontrasting

confidence: 70%

Reaction of Myeloperoxidase Compound I with Chloride, Bromide, Iodide, and Thiocyanate

1998

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“…Given that myeloperoxidase (MPO) is a critical effector of inflammation and abundantly expressed in neutrophils, monocytes and macrophages [ 58 ] its regulation in diclofenac treated animals was investigated. Moreover, diclofenac can be metabolized to reactive metabolites by MPO [ 59 ] which prompted our interest to investigate its expression. As depicted in Figure 11 (panel A1-A3) expression of MPO was basically absent in control animals.…”

Section: Resultsmentioning

confidence: 99%

The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

Selvaraj

Spanel

et al. 2017

Oncotarget

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Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes.Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system.

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“…A problem in measuring the enzyme chlorinating activity of MPO at pH 7 is the generation of the inactive compound I1 of MPO. Using an assay in which MCD is chlorinated, we showed that at neutral pH the high initial activity of MPO decreased after about 100 ms due to formation and accumulation of compound 11 [36]. Kettle and Winterbourn [37] showed that the monochlorodimedone used in the chlorination assay at neutral pH could be one of the components responsible for the conversion of active compound 1 into inactive compound 11.…”

Section: Discussionmentioning

confidence: 99%

“…Kettle and Winterbourn [37] showed that the monochlorodimedone used in the chlorination assay at neutral pH could be one of the components responsible for the conversion of active compound 1 into inactive compound 11. Inactivation could be prevented by the addition of 5-aminosalicylic acid, a reductant which is able to convert compound I1 rapidly back to active native enzyme [36]. Using the stopped-flow technique we measured the initial chlorinating activities of dimeric MPO and hemi-MPO at neutral pH in the presence or absence of 5-aminosalicylic acid.…”

Section: Discussionmentioning

confidence: 99%

Human hemi‐myeloperoxidase

Zuurbier

Berg

Gelder

et al. 1992

European Journal of Biochemistry

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Human neutrophilic myeloperoxidase (MPO) is involved in the defence mechanism of the body against micro-organisms. The enzyme catalyses the generation of the strong oxidant hypochlorous acid (HOC1) from hydrogen peroxide and chloride ions. In normal neutrophils MPO is present in the dimeric form (140 kDa). The disulphide-linked protomers each consist of a heavy subunit and a light one. Reductive alkylation converts the dimeric enzyme into two protomers, 'hemi-myeloperoxidase'.We studied the initial activities of human dimeric MPO and hemi-MPO at the physiological pH of 7.2 and found no significant differences in chlorinating activity. These results indicate that, at least at neutral pH, the protomers of MPO function independently. The absorption spectra of MPO compounds I1 and 111, both inactive forms concerning HOCl generation, and the rate constants of their formation were the same for dimeric MPO and hemi-MPO, but hemi-MPO required a slightly larger excess of HzOz for complete conversion. Hemi-MPO was less stable at a high temperature (SO'C) as compared to the dimeric enzyme. Furthermore, the resistance of the chlorinating activity of hemi-MPO against its oxidative product hypochlorous acid was somewhat lower (ICso = 32 pM HOC1) compared to dimeric MPO (ICs0 = 50 pM HOCl). The higher stability of dimeric MPO in the presence of its oxidative product compared to that of monomeric MPO might be the reason for the occurrence of MPO as a dimer.The enzyme myeloperoxidase (donor: H 2 0 2 oxidoreductase; MPO) is a major azurophil granule component of normal human ncutrophils and makes up 2 -5% of the total dry mass of these cells [l -41. MPO is involved in the defence mechanism against invading micro-organisms. In the presence of H202, which is generated from 0; produced by NADPH oxidase [5, 61, MPO so-called 'hemi-MPO' [18]. From kinetic studies of the chlorinating and peroxidase (in the absence of CI -) activities in the pH range of 4.4-6.2 of hemi-MPO (generated from normal dimeric MPO [20]), and of monomeric MPO (isolated from HL-60 cells [21]) no significant differences were found between dimeric enzyme, and hemi-or monomeric enzyme. At neutral pH, however, the peroxidase activities of monomeric MPO (79 kDa) [23], both isolated from human leukemia cells, were slightly lower as compared to those of the dimeric or 'large' MPO.Based on the assumption that dimcrization might confer higher catalytic activity or increased stability to the enzyme, we investigated and compared some properties of hemi-MPO with those of dimeric MPO. If the dimer was more stable or more active, this could explain its exclusive occurrence in normal human neutrophils. Besides chlorinating activity at a neutral physiological pH, we also examined compound I1 and compound 111 formation, since both compounds are inactive forms of MPO resulting from side-reactions in the catalytic process [24, 251. Furthermore, we investigated the heat stability and the resistance of both enzyme preparations towards their own product HOCl and the secondary oxid...

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Interaction of myeloperoxidase with diclofenac

Cited by 40 publications

References 34 publications

Reaction of Myeloperoxidase Compound I with Chloride, Bromide, Iodide, and Thiocyanate

Reaction of Myeloperoxidase Compound I with Chloride, Bromide, Iodide, and Thiocyanate

The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

Human hemi‐myeloperoxidase

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