Acetaminophen (paracetamol) inhibits myeloperoxidase-catalyzed oxidant production and biological damage at therapeutically achievable concentrations

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Show simple item record Koelsch, M Mallak, R Graham, G Kajer, T Milligan, MK Nguyen, LQ Newsham, DW Keh, JS Kettle, AJ Scott, KF Ziegler, JB Pattison, DI Fu, S Hawkins, CL Rees, MD Davies, MJ 2012-02-10T06:09:03Z 2010-01
dc.identifier.citation Biochemical Pharmacology, 2010, 79 (8), pp. 1156 - 1164
dc.identifier.issn 0006-2952
dc.identifier.other C1 en_US
dc.description.abstract The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H2O2) to catalyze the production of the potent oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) from halide and pseudohalide (SCN-) ions. These oxidants have been implicated as key mediators of tissue damage in many human inflammatory diseases including atherosclerosis, asthma, rheumatoid arthritis, cystic fibrosis and some cancers. It is shown here that acetaminophen (paracetamol), a phenol-based drug with analgesic and antipyretic actions, is an efficient inhibitor of HOCl and HOBr generation by isolated MPOH2O2halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC50) were 77 ± 6 µM (100 mM Cl-) and 92 ± 2 µM (100 mM Cl- plus 100 µM Br-), as measured by trapping of oxidants with taurine. The IC50 for inhibition of HOCl generation by human neutrophils was ca. 100 µM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (=150 µM) resulting from typical dosing regimes. Acetaminophen did not diminish superoxide generation by neutrophils, as measured by lucigenin-dependent chemiluminescence. Inhibition of HOCl production was associated with the generation of fluorescent acetaminophen oxidation products, consistent with acetaminophen acting as a competitive substrate of MPO. Inhibition by acetaminophen was maintained in the presence of heparan sulfate and extracellular matrix, materials implicated in the sequestration of MPO at sites of inflammation in vivo. Overall, these data indicate that acetaminophen may be an important modulator of MPO activity in vivo.
dc.publisher Pergamon-Elsevier Science Ltd
dc.relation.isbasedon 10.1016/j.bcp.2009.11.024
dc.title Acetaminophen (paracetamol) inhibits myeloperoxidase-catalyzed oxidant production and biological damage at therapeutically achievable concentrations
dc.type Journal Article
dc.parent Biochemical Pharmacology
dc.journal.volume 8
dc.journal.volume 79
dc.journal.number 8 en_US
dc.publocation United States en_US
dc.publocation New York
dc.identifier.startpage 1156 en_US
dc.identifier.endpage 1164 en_US SCI.Chemistry and Forensic Sciences en_US
dc.conference Verified OK en_US
dc.conference IEEE International Conference on Acoustics, Speech and Signal Processing
dc.for 1115 Pharmacology and Pharmaceutical Sciences
dc.personcode 103806
dc.percentage 100 en_US Pharmacology and Pharmaceutical Sciences en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US en_US 2006-05-14
dc.location.activity en_US
dc.location.activity Toulouse, France
dc.description.keywords Paracetamol, Acetaminophen, Myeloperoxidase, Oxidation, Neutrophil
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
pubs.organisational-group /University of Technology Sydney/Strength - Forensic Science
utslib.copyright.status Closed Access 2015-04-15 12:17:09.805752+10
pubs.consider-herdc true
utslib.collection.history Closed (ID: 3)
utslib.collection.history School of Chemistry and Forensic Science (ID: 339)

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