title: Mechanism of acetaminophen inhibition of cyclooxygenase isoforms.
abstract: Acetaminophen has similar analgesic and antipyretic properties to nonsteroidal antiinflammatory drugs (NSAIDs), which act via inhibition of cyclooxygenase enzymes. However, unlike NSAIDs, acetaminophen is at best weakly antiinflammatory. The mechanism by which acetaminophen exerts its therapeutic action has yet to be fully determined, as under most circumstances, acetaminophen is a very weak cyclooxygenase inhibitor. The potency of acetaminophen against both purified ovine cyclooxygenase-1 (oCOX-1) and human cyclooxygenase-2 (hCOX-2) was increased approximately 30-fold by the presence of glutathione peroxidase and glutathione to give IC50 values of 33 microM and 980 microM, respectively. Acetaminophen was found to be a good reducing agent of both oCOX-1 and hCOX-2. The results are consistent with a mechanism of inhibition of acetaminophen in which it acts to reduce the active oxidized form of COX to the resting form. Inhibition would therefore be more effective under conditions of low peroxide concentration, consistent with the known tissue selectivity of acetaminophen.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada. marc_ouellet@merck.com
authors.forename: M
authors.initials: M
authors.lastname: Ouellet
authors.forename: M D
authors.initials: MD
authors.lastname: Percival
mesh_terms: D000082:Acetaminophen / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000737:chemistry; D005979:Glutathione Peroxidase / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008041:Linoleic Acids / Q000737:chemistry; D008054:Lipid Peroxides / Q000737:chemistry; D008565:Membrane Proteins; D010084:Oxidation-Reduction / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D019163:Reducing Agents / Q000737:chemistry / Q000494:pharmacology; D012756:Sheep
chemical_list: D007527:Isoenzymes; D008041:Linoleic Acids; D008054:Lipid Peroxides; D008565:Membrane Proteins; D019163:Reducing Agents; C038649:13-hydroperoxy-9,11-octadecadienoic acid; D000082:Acetaminophen; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; D007052:Ibuprofen; D007213:Indomethacin