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

Abstract

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. cardiovascular side effect | coxib | eicosanoids | metabolomics | Vioxx

Effect of Cigarette Smoking on the Production of 20-Hydroxyeicosatetraenoic Acid in Human Platelet

“…21 Interestingly, 20-HETE was reported to activate platelet aggregation through ADP dependent mechanism. 7 This might indicate that elevated 20-HETE in smoker platelets plays, at least in part, a role in alteration of antiplatelet drug response. It is recommended to investigate the effect of 20-HETE synthesis inhibitors on the response of antiplatelet drugs.…”

“…It is a hypertensive chemical and increases platelet aggregation. 7 Elevated plasma 20-HETE levels was observed among human cardiovascular patients. 18 In this study, the results showed that 20-HETE levels were higher in clinical plasma and platelet samples from smokers.…”

“…4 These cigarette compounds were reported to induce some cytochrome (CYP) P450s in liver, lung and gastrointestinal tract. 5,6 Liu et al 7 , pointed out that 20-hydroxyeicosatetraenoic acid (20-HETE) is a platelet activator and showed that elevated plasma levels of 20-HETE were associated with decreased bleeding time. 7 The 20-HETE is an arachidonic acid metabolite, which is synthesized mainly through CYP4A and CYP4F subfamilies.…”

“…5,6 Liu et al 7 , pointed out that 20-hydroxyeicosatetraenoic acid (20-HETE) is a platelet activator and showed that elevated plasma levels of 20-HETE were associated with decreased bleeding time. 7 The 20-HETE is an arachidonic acid metabolite, which is synthesized mainly through CYP4A and CYP4F subfamilies. 8 The expression and the activity of arachidonic acid metabolizingCYPs had been identified in human platelets.…”

Synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl and sulfamoyl acetamides and ethyl acetates as potent COX-2 inhibitors

“…4 Nevertheless, some studies have suggested that rofecoxib's adverse cardiac events may be related to its chemical structure. In fact, rofecoxib can readily form a reactive metabolite, which in turn can disrupt essential cellular structure by reacting with nucleophilic groups of various biologic molecules, 5 suggesting that adverse cardiac events might not be a class-related effect. Therefore, novel scaffolds with selective COX-2 inhibitory activity are needed.…”