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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{sub 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.more » 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.« less

Authors:
; ; ; ; ; ; ; ; ;  [1]
  1. (Michigan)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002241
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. USA; Journal Volume: 107; Journal Issue: (1) ; 01, 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; ACETYLSALICYLIC ACID; ARACHIDONIC ACID; CATALYSIS; DIMERS; IN VITRO; INFLAMMATION; MONOMERS; PROCESSING; PROSTAGLANDINS; SIDE EFFECTS; TARGETS; THROMBOSIS

Citation Formats

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., and Smith, William L.. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. United States: N. p., 2010. Web. doi:10.1073/pnas.0909765106.
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.. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. United States. doi:10.1073/pnas.0909765106.
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., and Smith, William L.. Thu . "Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1". United States. doi:10.1073/pnas.0909765106.
@article{osti_1002241,
title = {Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1},
author = {Rimon, Gilad and Sidhu, Ranjinder S. and Lauver, D. Adam and Lee, Jullia Y. and Sharma, Narayan P. and Yuan, Chong and Frieler, Ryan A. and Trievel, Raymond C. and Lucchesi, Benedict R. and Smith, William L.},
abstractNote = {Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A{sub 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.},
doi = {10.1073/pnas.0909765106},
journal = {Proc. Natl. Acad. Sci. USA},
number = (1) ; 01, 2010,
volume = 107,
place = {United States},
year = {Thu Feb 11 00:00:00 EST 2010},
month = {Thu Feb 11 00:00:00 EST 2010}
}