{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T14:02:29Z","timestamp":1783519349440,"version":"3.55.0"},"reference-count":43,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,7,1]]},"abstract":"<jats:p>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\u00a0\u03bcM respectively. Structure\u2013activity 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.<\/jats:p>","DOI":"10.1042\/bj20090309","type":"journal-article","created":{"date-parts":[[2009,4,20]],"date-time":"2009-04-20T15:34:38Z","timestamp":1240241678000},"page":"79-86","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides"],"prefix":"10.1042","volume":"421","author":[{"given":"Martin\u00a0D.","family":"Rees","sequence":"first","affiliation":[{"name":"The Heart Research Institute, 114 Pyrmont Bridge Rd, Camperdown, Sydney, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven\u00a0E.","family":"Bottle","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn\u00a0E.","family":"Fairfull-Smith","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst","family":"Malle","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Graz 8010, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u00a0M.","family":"Whitelock","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Engineering, University of New South Wales, Kensington, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0J.","family":"Davies","sequence":"additional","affiliation":[{"name":"The Heart Research Institute, 114 Pyrmont Bridge Rd, Camperdown, Sydney, NSW 2050, Australia"},{"name":"Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2009,6,12]]},"reference":[{"key":"2021112217212854800_B1","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1182\/blood.V92.9.3007","article-title":"Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing","volume":"92","author":"Hampton","year":"1998","journal-title":"Blood"},{"key":"2021112217212854800_B2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.abb.2005.07.005","article-title":"Bromination and chlorination reactions of myeloperoxidase at physiological concentrations of bromide and chloride","volume":"445","author":"Senthilmohan","year":"2006","journal-title":"Arch. 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