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

Gilad Rimon, Ranjinder S. Sidhu, D. Adam Lauver, Jullia Y. Lee, Narayan P. Sharma, Chong Yuan, Ryan A. Frieler, Raymond C. Trievel, Benedict R. Lucchesi, William L. Smith

    Research output: Contribution to journalArticlepeer-review

    156 Scopus citations

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)28-33
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number1
    DOIs
    StatePublished - 15 Feb 2010

    Keywords

    • Adrenic acid
    • Arachidonic acid
    • Nonsteroidal antiinflammatory drugs
    • Platelet
    • Prostaglandin

    ASJC Scopus subject areas

    • General

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