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

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.

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Available from: Jun Yang, Sep 27, 2015
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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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    ABSTRACT: Diabetes is characterized by hyperglycemia and development of vascular pathology. Endothelial cell dysfunction is a starting point for pathogenesis of vascular complications in diabetes. We previously showed the polyol erythritol to be a hydroxyl radical scavenger preventing endothelial cell dysfunction onset in diabetic rats. To unravel mechanisms, other than scavenging of radicals, by which erythritol mediates this protective effect, we evaluated effects of erythritol in endothelial cells exposed to normal (7 mM) and high glucose (30 mM) or diabetic stressors (e.g. SIN-1) using targeted and transcriptomic approaches. This study demonstrates that erythritol (i.e. under non-diabetic conditions) has minimal effects on endothelial cells. However, under hyperglycemic conditions erythritol protected endothelial cells against cell death induced by diabetic stressors (i.e. high glucose and peroxynitrite). Also a number of harmful effects caused by high glucose, e.g. increased nitric oxide release, are reversed. Additionally, total transcriptome analysis indicated that biological processes which are differentially regulated due to high glucose are corrected by erythritol. We conclude that erythritol protects endothelial cells during high glucose conditions via effects on multiple targets. Overall, these data indicate a therapeutically important endothelial protective effect of erythritol under hyperglycemic conditions.
    PLoS ONE 06/2013; 8(6):e65741. DOI:10.1371/journal.pone.0065741 · 3.23 Impact Factor
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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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    ABSTRACT: Bacteria colonizing the human intestinal tract exhibit a high phylogenetic diversity that reflects their immense metabolic potentials. The catalytic activity of gut microbes has an important impact on gastrointestinal (GI) functions and host health. The microbial conversion of carbohydrates and other food components leads to the formation of a large number of compounds that affect the host metabolome and have beneficial or adverse effects on human health. Metabolomics is a metabolic-biology system approach focused on the metabolic responses understanding of living systems to physio-pathological stimuli by using multivariate statistical data on human body fluids obtained by different instrumental techniques. A metabolomic approach based on an analytical platform could be able to separate, detect, characterize and quantify a wide range of metabolites and its metabolic pathways. This approach has been recently applied to study the metabolic changes triggered in the gut microbiota by specific diet components and diet variations, specific diseases, probiotic and synbiotic food intake. This review describes the metabolomic data obtained by analyzing human fluids by using different techniques and particularly Gas Chromatography Mass Spectrometry Solid-phase Micro Extraction (GC-MS/SPME), Proton Nuclear Magnetic Resonance ((1)H-NMR) Spectroscopy and Fourier Transform Infrared (FTIR) Spectroscopy. This instrumental approach has a good potential in the identification and detection of specific food intake and diseases biomarkers.
    Frontiers in Cellular and Infection Microbiology 12/2012; 2:156. DOI:10.3389/fcimb.2012.00156 · 3.72 Impact Factor
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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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    ABSTRACT: Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF)-diet-induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH-null mice showed lower diet-induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term) or 16 weeks (long-term) and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet-increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet-induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet-induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet-induced hepatic steatosis in inhibiting systemic inflammation.
    PLoS ONE 06/2012; 7(6):e39165. DOI:10.1371/journal.pone.0039165 · 3.23 Impact Factor
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