Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides |
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| Institution: | 1. Heart Research Institute, Newtown, Sydney, NSW 2042, Australia;2. Faculty of Medicine, University of Sydney, Sydney, NSW, Australia;3. School of Physical and Chemical Sciences, Queensland University of Technology, Brisbane, QLD, Australia;4. Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Kyushu, Japan;5. Centre for Forensic Science, University of Technology, Sydney, NSW, Australia;1. Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, United States;2. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China;1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC;2. Department of Orthopedics, Taipei Medical University Hospital, Taipei, Taiwan, ROC;3. Department of Orthopedics, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC;4. Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan, ROC;5. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC;6. Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC;1. Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Høegh-Guldbergs Gade 6B, 8000 Aarhus C, Denmark;2. Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark;3. Leibniz Institute für Molekulare Pharmakologie (FMP), NMR Supported Structural Biology, Robert Roessle Str. 10, 13125 Berlin, Germany;1. ARC Centre of Excellence for Free Radical Chemistry, Faculty of Science and Engineering, Queensland University of Technology (QUT), Brisbane, Queensland, Australia;2. Cell and Molecular Biology, Queensland Institute of Medical Research, Brisbane, Australia;3. School of Chemistry, University of Sydney, Australia;4. University of Queensland, Centre for Clinical Research, Brisbane, Australia;5. Queensland Eye Institute, South Brisbane, Australia;6. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK;1. Department of Polymer Science, University of Madras, Guindy Campus, Chennai, India;2. Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India;3. NMR, Inorganic and Physical Chemistry Laboratory, CSIR-Central Leather Research Institute, Chennai, India |
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| Abstract: | The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, −OCl) generated by the myeloperoxidase (MPO)–H2O2–Cl− system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79–86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89–99% decreased rate of reduction) and activated human neutrophils (62–75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed. |
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| Keywords: | Myeloperoxidase Neutrophil Nitroxide Hypochlorous acid Superoxide radicals Protein oxidation Free radicals |
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