Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events

Department of Entomology and University of California-Davis Cancer Center, University of California, Davis, CA 95616, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2010; 107(39):17017-22. DOI: 10.1073/pnas.1011278107
Source: PubMed


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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    • "Eicosanoids (or oxylipins) derived from cyclooxygenase-, lipoxygenase- and cytochrome P450- enzymes, including those associated with hypertension and ED, were measured after published methods [16], [17] in cell pellets (nmol/g protein) and culture medium (nM). The 23 eicosanoids measured included 12,13-DiHOME, 9,10-DiHOME, 14,15-DiHETrE, 11,12-DiHETrE, 8,9-DiHETrE, 5,6-DiHETrE, 9(10)-EpOME, 12(13)-EpOME, 14(15)-EpETrE, 11(12)-EpETrE, 8(9)-EpETrE, 5(6)-EpETrE, TXB2, PGE2, PGD2, PGF2α, LTB4, 5-HETE, 8-HETE, 11-HETE, 12-HETE, and 15-HETE [for abbreviations, see Table S1 in [18]]. "
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    • "The recent rapid development of a range of analytical platforms, including gas chromatography (GC), liquid chromatography (LC), high pressure LC (HPLC), ultra pressure LC (UPLC) coupled to mass spectrometry (MS), capillary electrophoresis (CE) coupled to MS, Fourier Transform Infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) [e.g., proton ( 1 H)-NMR] spectroscopy , can enable to separate, detect, characterize, and quantify such metabolites and related metabolic pathways (Zhang et al., 2011). Metabolomics focuses on the complex interactions of system components and highlights the whole system rather than the individual parts, providing a distinct perspective on cellular homeostasis (Liu et al., 2010). Even if nowadays NMR, GC-MS, LC-MS are the prevalent techniques used, none of them is a perfect technique that can meet the requirements of metabolomics for measuring all metabolites. "
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    • "Moreover, sEH inhibition or overexpression might result in a shift of arachidonic acid metabolic pathways: with one pathway inhibited, other pathways may be activated. Using a metabolomic approach, we previously demonstrated that chronic administration of a selective cyclooxygenase 2 inhibitor resulted in >120-fold increase in blood level of 20-hydroxyeicosatetraenoic acid, a cytochrome P450 (CYP450) metabolite of arachidonic acid [36]. In addition, omega-3 polyunsaturated fatty acids are substrates of CYP450 epoxgenases [37], and the epoxy products of DHA and EPA could be hydrolyzed by sEH. "
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