title: Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.
abstract: Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.
authors: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 4810, USA.
authors: Gilad
authors: G
authors: Rimon
authors: Ranjinder S
authors: RS
authors: Sidhu
authors: D Adam
authors: DA
authors: Lauver
authors: Jullia Y
authors: JY
authors: Lee
authors: Narayan P
authors: NP
authors: Sharma
authors: Chong
authors: C
authors: Yuan
authors: Ryan A
authors: RA
authors: Frieler
authors: Raymond C
authors: RC
authors: Trievel
authors: Benedict R
authors: BR
authors: Lucchesi
authors: William L
authors: WL
authors: Smith
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001241:Aspirin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D010975:Platelet Aggregation Inhibitors; D021122:Protein Subunits; D051545:Cyclooxygenase 1; D001241:Aspirin