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.
Skip Nav Destination
Article navigation
July 2009
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
June 12 2009
Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides
Martin D. Rees;
Martin D. Rees
1
*The Heart Research Institute, 114 Pyrmont Bridge Rd, Camperdown, Sydney, NSW 2050, Australia
1To whom correspondence should be addressed (email reesm@hri.org.au).
Search for other works by this author on:
Steven E. Bottle;
Steven E. Bottle
†Australian Research Council Centre of Excellence for Free Radical Chemistry and Biotechnology, School of Physical and Chemical Sciences, Queensland University of Technology, GPO Box 2434, Brisbane, Queensland 4001, Australia
Search for other works by this author on:
Kathryn E. Fairfull-Smith;
Kathryn E. Fairfull-Smith
†Australian Research Council Centre of Excellence for Free Radical Chemistry and Biotechnology, School of Physical and Chemical Sciences, Queensland University of Technology, GPO Box 2434, Brisbane, Queensland 4001, Australia
Search for other works by this author on:
Ernst Malle;
Ernst Malle
‡Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Graz 8010, Austria
Search for other works by this author on:
John M. Whitelock;
John M. Whitelock
§Graduate School of Biomedical Engineering, University of New South Wales, Kensington, Sydney, NSW 2052, Australia
Search for other works by this author on:
Michael J. Davies
Michael J. Davies
*The Heart Research Institute, 114 Pyrmont Bridge Rd, Camperdown, Sydney, NSW 2050, Australia
∥Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
February 24 2009
Revision Received:
April 06 2009
Accepted:
April 20 2009
Accepted Manuscript online:
April 20 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 421 (1): 79–86.
Article history
Received:
February 24 2009
Revision Received:
April 06 2009
Accepted:
April 20 2009
Accepted Manuscript online:
April 20 2009
Citation
Martin D. Rees, Steven E. Bottle, Kathryn E. Fairfull-Smith, Ernst Malle, John M. Whitelock, Michael J. Davies; Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides. Biochem J 1 July 2009; 421 (1): 79–86. doi: https://doi.org/10.1042/BJ20090309
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.