TY - JOUR

T1 - Acetaminophen (paracetamol) inhibits myeloperoxidase-catalyzed oxidant production and biological damage at therapeutically achievable concentrations

AU - Koelsch, Maud

AU - Mallak, Roger

AU - Graham, Garry G

AU - Kajer, Tracey

AU - Milligan, Marian K

AU - Nguyen, Ly Q

AU - Newsham, Dawn W

AU - Keh, Jeremy S

AU - Kettle, Anthony J

AU - Scott, Kieran F

AU - Ziegler, John B

AU - Pattison, David I

AU - Fu, Shanlin

AU - Hawkins, Clare Louise

AU - Rees, Martin D

AU - Davies, Michael Jonathan

N1 - 2009 Elsevier Inc. All rights reserved.

PY - 2010/4/15

Y1 - 2010/4/15

N2 - The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H(2)O(2)) 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-H(2)O(2)-halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC(50)) were 77+/-6microM (100mMCl(-)) and 92+/-2microM (100mMCl(-) plus 100microMBr(-)), as measured by trapping of oxidants with taurine. The IC(50) for inhibition of HOCl generation by human neutrophils was ca. 100microM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (< or =150microM) 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.

AB - The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H(2)O(2)) 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-H(2)O(2)-halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC(50)) were 77+/-6microM (100mMCl(-)) and 92+/-2microM (100mMCl(-) plus 100microMBr(-)), as measured by trapping of oxidants with taurine. The IC(50) for inhibition of HOCl generation by human neutrophils was ca. 100microM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (< or =150microM) 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.

KW - Acetaminophen

KW - Analgesics, Non-Narcotic

KW - Bromates

KW - Catalysis

KW - Humans

KW - Hypochlorous Acid

KW - Neutrophils

KW - Oxidants

KW - Peroxidase

KW - Superoxides

U2 - 10.1016/j.bcp.2009.11.024

DO - 10.1016/j.bcp.2009.11.024

M3 - Journal article

C2 - 19968966

VL - 79

SP - 1156

EP - 1164

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 8

ER -