Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

Research output: Contribution to journalJournal articleResearchpeer-review

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Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides. / Rees, Martin D; Bottle, Steven E; Fairfull-Smith, Kathryn E; Malle, Ernst; Whitelock, John M; Davies, Michael Jonathan.

In: Biochemical Journal, Vol. 421, No. 1, 01.07.2009, p. 79-86.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Rees, MD, Bottle, SE, Fairfull-Smith, KE, Malle, E, Whitelock, JM & Davies, MJ 2009, 'Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides', Biochemical Journal, vol. 421, no. 1, pp. 79-86. https://doi.org/10.1042/BJ20090309

APA

Rees, M. D., Bottle, S. E., Fairfull-Smith, K. E., Malle, E., Whitelock, J. M., & Davies, M. J. (2009). Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides. Biochemical Journal, 421(1), 79-86. https://doi.org/10.1042/BJ20090309

Vancouver

Rees MD, Bottle SE, Fairfull-Smith KE, Malle E, Whitelock JM, Davies MJ. Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides. Biochemical Journal. 2009 Jul 1;421(1):79-86. https://doi.org/10.1042/BJ20090309

Author

Rees, Martin D ; Bottle, Steven E ; Fairfull-Smith, Kathryn E ; Malle, Ernst ; Whitelock, John M ; Davies, Michael Jonathan. / Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides. In: Biochemical Journal. 2009 ; Vol. 421, No. 1. pp. 79-86.

Bibtex

@article{72ccd8a8a130476785bd482645ce73f3,
title = "Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides",
abstract = "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 microM 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.",
keywords = "Heme, Humans, Hydroxylamines, Hypochlorous Acid, Molecular Sequence Data, Neutrophils, Nitrogen Oxides, Oxidation-Reduction, Peroxidase",
author = "Rees, {Martin D} and Bottle, {Steven E} and Fairfull-Smith, {Kathryn E} and Ernst Malle and Whitelock, {John M} and Davies, {Michael Jonathan}",
year = "2009",
month = "7",
day = "1",
doi = "10.1042/BJ20090309",
language = "English",
volume = "421",
pages = "79--86",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

AU - Rees, Martin D

AU - Bottle, Steven E

AU - Fairfull-Smith, Kathryn E

AU - Malle, Ernst

AU - Whitelock, John M

AU - Davies, Michael Jonathan

PY - 2009/7/1

Y1 - 2009/7/1

N2 - 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 microM 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.

AB - 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 microM 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.

KW - Heme

KW - Humans

KW - Hydroxylamines

KW - Hypochlorous Acid

KW - Molecular Sequence Data

KW - Neutrophils

KW - Nitrogen Oxides

KW - Oxidation-Reduction

KW - Peroxidase

U2 - 10.1042/BJ20090309

DO - 10.1042/BJ20090309

M3 - Journal article

VL - 421

SP - 79

EP - 86

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 1

ER -

ID: 129670412