Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 39, Pages 17017-17022Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1011278107
Keywords
cardiovascular side effect; coxib; eicosanoids; metabolomics; Vioxx
Categories
Funding
- National Institute of Environmental Health Sciences [ES02710, P42 ES04699]
- National Heart, Lung, and Blood Institute [HL85727, HL85844]
- Major National Basic Research Grant of China [2010CB912504]
- Cystic Fibrosis Foundation, Inc.
- Veterans Affairs
- American Heart Association
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Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX-mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE's degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib.
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