Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 1; pp. 28 - 33
• Main Authors: Rimon, Gilad, Sidhu, Ranjinder S, Lauver, D. Adam, Lee, Jullia Y, Sharma, Narayan P, Yuan, Chong, Frieler, Ryan A, Trievel, Raymond C, Lucchesi, Benedict R, Smith, William L
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.01.2010; National Acad Sciences
• Subjects: 60 APPLIED LIFE SCIENCES; ACETYLSALICYLIC ACID; Active sites; adverse effects; analgesia; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; ARACHIDONIC ACID; Aspirin; Aspirin - chemistry; Aspirin - metabolism; Aspirin - pharmacology; Atoms; Binding sites; Biological Sciences; cardioprotective effect; CATALYSIS; catalytic activity; Catalytic Domain; Crystal structure; Crystallography, X-Ray; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase inhibitors; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - metabolism; Cyclooxygenase Inhibitors - pharmacology; DIMERS; Dogs; Enzymes; Fatty acids; Humans; IN VITRO; INFLAMMATION; Isoenzymes - chemistry; Isoenzymes - metabolism; Models, Molecular; MONOMERS; Nonsteroidal anti-inflammatory drugs; Pain; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - metabolism; Platelet Aggregation Inhibitors - pharmacology; Platelets; PROCESSING; prostaglandin synthase; PROSTAGLANDINS; Protein Binding; Protein Conformation; Protein Subunits - chemistry; Protein Subunits - metabolism; Protein synthesis; SIDE EFFECTS; TARGETS; Thromboembolism; THROMBOSIS; X-ray diffraction
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0909765106

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A₂ 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.