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

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dc.contributor.author Koelsch, Maud en_US
dc.contributor.author Mallak, Roger en_US
dc.contributor.author Graham, Garry en_US
dc.contributor.author Kajer, Tracey en_US
dc.contributor.author Milligan, Marian en_US
dc.contributor.author Nguyen, Ly en_US
dc.contributor.author Newsham, Dawn en_US
dc.contributor.author Keh, Jeremy en_US
dc.contributor.author Kettle, Anthony en_US
dc.contributor.author Scott, Kieran en_US
dc.contributor.author Ziegler, John en_US
dc.contributor.author Pattison, David en_US
dc.contributor.author Fu, Shanlin en_US
dc.contributor.author Hawkins, Clare en_US
dc.contributor.author Rees, Martin en_US
dc.contributor.author Davies, Michael en_US
dc.contributor.editor en_US
dc.date.accessioned 2012-02-10T06:09:03Z
dc.date.available 2012-02-10T06:09:03Z
dc.date.issued 2010 en_US
dc.identifier 2010003304 en_US
dc.identifier.citation Koelsch Maud et al. 2010, 'Acetaminophen (paracetamol) inhibits myeloperoxidase-catalyzed oxidant production and biological damage at therapeutically achievable concentrations', Pergamon-Elsevier Science Ltd, vol. 79, no. 8, pp. 1156-1164. en_US
dc.identifier.issn 0006-2952 en_US
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/16898
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 MPO?H2O2?halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC50) were 77 ? 6 ?M (100 mM Cl-) and 92 ? 2 ?M (100 mM Cl- plus 100 ?M Br-), as measured by trapping of oxidants with taurine. The IC50 for inhibition of HOCl generation by human neutrophils was ca. 100 ?M. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (=150 ?M) 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. en_US
dc.language en_US
dc.publisher Pergamon-Elsevier Science Ltd en_US
dc.relation.isbasedon http://dx.doi.org/10.1016/j.bcp.2009.11.024 en_US
dc.title Acetaminophen (paracetamol) inhibits myeloperoxidase-catalyzed oxidant production and biological damage at therapeutically achievable concentrations en_US
dc.parent Biochemical Pharmacology en_US
dc.journal.volume 79 en_US
dc.journal.number 8 en_US
dc.publocation United States en_US
dc.identifier.startpage 1156 en_US
dc.identifier.endpage 1164 en_US
dc.cauo.name SCI.Chemistry and Forensic Sciences en_US
dc.conference Verified OK en_US
dc.for 111500 en_US
dc.personcode 0000067466 en_US
dc.personcode 0000067467 en_US
dc.personcode 0000067469 en_US
dc.personcode 10422145 en_US
dc.personcode 0000067470 en_US
dc.personcode 0000067471 en_US
dc.personcode 0000067472 en_US
dc.personcode 0000067473 en_US
dc.personcode 0000067474 en_US
dc.personcode 0000067475 en_US
dc.personcode 0000067476 en_US
dc.personcode 0000067477 en_US
dc.personcode 103806 en_US
dc.personcode 0000045886 en_US
dc.personcode 0000067479 en_US
dc.personcode 0000045917 en_US
dc.percentage 100 en_US
dc.classification.name Pharmacology and Pharmaceutical Sciences en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity en_US
dc.description.keywords Paracetamol, Acetaminophen, Myeloperoxidase, Oxidation, Neutrophil en_US


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