Biological activity and metabolism of 20‐hydroxyeicosatetraenoic acid in the human platelet

Hill, Elizabeth M.; Fitzpatrick, F. A.; Murphy, Robert C.

doi:10.1111/j.1476-5381.1992.tb14327.x

Cited by 55 publications

(32 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…phospholipase treatment and inhibits the ARA A23187-and U46619-induced human platelet aggregation at the concentrations of 10 and 30 μM, respectively, in a dose-dependent manner (29,38). However, 20-HETE had no detectable agonist activity on human platelets at a concentration less than 30 μM (29).…”

Section: Discussionmentioning

confidence: 99%

“…S2 C and D) argues that biosynthesis of 20-HETE is not altered. 20-HETE has been demonstrated to be further metabolized by COX to 20-hydroxy PGs (e.g., 20-OH-PGE 2 , 20-OH-PGF 2α ) and other mediators (29)(30)(31) in in vitro studies. Thus, the 20-HETE increase both in vivo and in vitro could be explained by blocking one of its major routes of degradative metabolism pathways using rofecoxib.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Liu

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

102

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Liu

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

102

View full text Add to dashboard Cite

show abstract

“…58 In platelets and polymorphonuclear leukocytes, 20-HETE can be metabolized by lipoxygenases and COX to inactive products. 61,62 CYP epoxygenases, such as CYP2C23, metabolize 20-HETE to 20-hydroxy-epoxyeico-satrienoic acid (EETs) in rat kidney, which have been shown to act as PPARα activators 63 and contribute to the anti-inflammatory and protective properties of lipid-lowering drugs. 64 In the liver and kidney, 20-HETE is esterified into phospholipids and stored.…”

Section: -Hete Biosynthesis Metabolism and Releasementioning

confidence: 99%

20-HETE and Blood Pressure Regulation

Wu¹,

Gupta

García

et al. 2014

Cardiology in Review

126

148

View full text Add to dashboard Cite

20-Hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE) is a cytochrome P450 (CYP)–derived omega-hydroxylation metabolite of arachidonic acid. 20-HETE has been shown to play a complex role in blood pressure regulation. In the kidney tubules, 20-HETE inhibits sodium reabsorption and promotes natriuresis, thus, contributing to antihypertensive mechanisms. In contrast, in the microvasculature, 20-HETE has been shown to play a pressor role by sensitizing smooth muscle cells to constrictor stimuli and increasing myogenic tone, and by acting on the endothelium to further promote endothelial dysfunction and endothelial activation. In addition, 20-HETE induces endothelial angiotensin-converting enzyme, thus, setting forth a potential feed forward prohypertensive mechanism by stimulating the renin–angiotensin–aldosterone system. With the advancement of gene sequencing technology, numerous polymorphisms in the regulatory coding and noncoding regions of 20-HETE–producing enzymes, CYP4A11 and CYP4F2, have been associated with hypertension. This in-depth review article discusses the biosynthesis and function of 20-HETE in the cardiovascular system, the pharmacological agents that affect 20-HETE action, and polymorphisms of CYP enzymes that produce 20-HETE and are associated with systemic hypertension in humans.

show abstract

“…14 15 It is converted by COX to a vasoconstrictor prostaglandin H 2 (PGH 2 ) analogue (20-OH PGH 2 ) that undergoes additional transformation by isomerases to vasodilator/diuretic metabolites (20-OH PGE 2 , 20-OH PGI 2 ) and vasoconstrictor/antidiuretic metabolites (20-OH TXA 2 , 20-OH PGF 2α ) 16…”

Section: Features Of Cyp Related 20-hete Metabolismmentioning

confidence: 99%