Epoxyeicosatrienoic acid
The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of
Structure
EETS are epoxide eicosatrienoic acid metabolites of arachidonic acid (a straight chain eicosatetraenoic acid, omega-6 fatty acid). Arachidonic acid has 4 cis double bonds (see Cis–trans isomerism), which are abbreviated with the notation Z in the IUPAC chemical nomenclature used here. These double bonds are located between carbons 5–6, 8–9, 11–12, and 14–15; arachidonic acid is therefore 5Z,8Z,11Z,14Z-eicosatetraenoic acid. Cytochrome P450 epoxygenases attack these double bonds to form their respective eicosatrienoic acid epoxide regioisomers (see Structural isomer § Position isomerism (regioisomerism)) viz., 5,6-EET (i.e. 5,6-epoxy-8Z,11Z,14Z-eicosatrienoic acid), 8,9-EET (i.e. 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid), 11,12-EET (i.e. 11,12-epoxy-5Z,8Z,14Z-eicosatrienoic acid), or, as drawn in the attached figure, 14,15-EET (i.e. 14,15-epoxy-5Z,8Z,11Z-eicosatrienoic acid). The enzymes generally form both R/S enantiomers at each former double bond position; for example, cytochrome P450 epoxidases metabolize arachidonic acid to a mixture of 14R,15S-EET and 14S,15R-EET.[4]
Production
The
ETEs are commonly produced by the stimulation of specific cell types. The stimulation causes arachidonic acid to be released from the sn-2 position of cellular phospholipids through the action of phospholipase A2-type enzymes and subsequent attack of the released arachidonic acid by a CYP epoxidase.[4] In a typical example of this mechanism, bradykinin or acetylcholine acting through their respective bradykinin receptor B2 and muscarinic acetylcholine receptor M1 or muscarinic acetylcholine receptor M3 stimulate vascular endothelial cells to make and release EETs.[9]
The CYP epoxygenases, similar to essentially all CYP450 enzymes, are involved in the metabolism of diverse
Metabolism of EETs
In cells, the EETs are rapidly metabolized by a cytosolic
Membrane-bound microsomal epoxide hydrolase (mEH or epoxide hydrolase 1 [EC 3.2.2.9.]) can metabolize EETs to their dihydroxy products but is regarded as not contributing significantly to EET inactivation in vivo except perhaps in brain tissue where mEH activity levels far outstrip those of sEH.[13][14] Furthermore, two other human sEH, epoxide hydrolases 3 and 4 (see Epoxide hydrolase), have been defined but their role in attacking EETs (and other epoxides) in vivo has not yet been determined. Besides these four epoxide hydrolase pathways, EETs may be acylated into phospholipids in an acylation-like reaction. This pathway may serve to limit the action of EETs or store them for future release.[4] EETs are also inactivated by being further metabolized through three other pathways: beta oxidation, omega oxidation, and elongation by enzymes involved in fatty acid synthesis.[13][15] These alternate to sEH pathways of EET metabolism ensure that blockade of sEH with drugs can increase EET levels only moderately in vivo.[14]
Biological effects
Generally, EETs cause:
- Calcium release from intracellular stores[1]
- Increased sodium-hydrogen antiporter activity[1]
- Increased cell proliferation[1]
- Decreased cyclooxygenase activity[1]
Other effects are specific to certain cells or locations; EETs:
- Are cardioprotective after ischemic heart attack and reperfusion.[16]
- Act in the corpus cavernosum to maintain penile erection.[17]
- Specific epoxidation of EET sites produces endogenous PPARα agonists.[18]
- Decrease release of somatostatin, insulin and glucagon from endocrine cells.[1]
- Stimulate blood vessel formation (angiogenesis).[1]
- Cause vasodilation in the systemic arterial circulation.[1]
- Cause vasoconstriction of the liver sinusoidal and pulmonary venous systems.[19]
- Increased risk of endothelial cells.[1]
- Decrease platelet aggregation responses.[1]
- Increase axon growth in neurons.[13]
Diol metabolites of the EETs, i.e. the diHETrEs (also termed DHETs), have relatively little or no activity compared to the EETs in most systems. However:
- The chemotaxis response of human monocytes to monocyte chemotactic protein 1) in vivo and in vitro appears to depend on the generation of EETs and conversion of these EETs to diHETrEs.[13]
- Certain diHETrEs dilate human coronary arteries with efficacies approaching those of the EETs.[20]
- 11,12-diHETrE but not 11,12-EET appears to support the maturation of the myelocyte cell line (i.e. support myelopoiesis) in mice and to promote certain types of angiogenesis in mice and zebrafish.[21]
- In opposition of the anti-inflammatory actions of EETs, diHETrEs may have some pro-inflammatory actions.[22]
Clinical significance
Regulation of blood pressure
With respect to the regulation of blood pressure as well as the kidneys' regulation of salt and water absorption (which contributes to blood pressure regulation), EETS are counterpoises to another CYP-derived arachidonic acid metabolite,
In humans, vascular endothelium production of EETs involves mainly CYP2C9 and numerous indirect studies have implicated CYP epoxygenase, possibly CYP2C9, in producing a product which causes vasodilation. These studies find that selective (but not entirely specific) CYP epoxygenase-inhibiting drugs reduce human vasodilation responses elicited by the vasodilators
While many of the cited studies suggest that one or more of the EETs released by vascular endothelial cells are responsible for the actions of the vasodilators and that deficiencies in EET production or excessive EET inactivation by sEH underlie certain types of hypertension in humans, they are not conclusive. They do not exclude a possibility that other polyunsaturated fatty acid epoxides such as those derived from eicosatetraenoic, docosatetraenoic, or linoleic acids made by CYP2C9 or other CYP epoxygenases (see
As indicated on the ClinicalTrials.gov web site, a National Institutes of Health-sponsored clinical trial entitled "Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance" has not been completed or reported on although started in 2009.[30]
Heart disease
As indicated elsewhere on this page, EETs inhibit inflammation, inhibit
Humans with established coronary artery disease have higher levels of plasma EETs and higher ratios of 14,15-EET to 14,15-diHETrE (14,15-diHETrE is the less active or inactive metabolite 14,15-EET). This suggests that the EETs serve a protective role in this setting and that these plasma changes were a result of a reduction in cardiac sEH activity. Furthermore, coronary artery disease patients who had lower levels of EETs/14,15-di-ETE ratios exhibited evidence of a poorer prognosis based on the presence of poor prognostic indicators, cigarette smoking, obesity, old age, and elevation in inflammation markers.[3][31]
Strokes and seizures
Indirect studies in animal models suggest that EETs have protective effects in
sEH inhibitors and gene knockout also reduce the number and severity of
Portal hypertension
Portal hypertension or hypertension in the venous
Cancer
The forced over-expression of CYP2J2 in or the addition of an EET to cultured human Tca-8113 oral squamous cancer cells, lung cancer
Studies of the CYP epoxygenases have not been restricted to the CYP2J subfamily. Reduction in the expression of CYP3A4 or CYP2C using small interfering RNA inhibits the growth of cultured
The cited findings suggest that various CYP epoxygenases along with the epoxide metabolites which they make promote the growth and spread of diverse types of cancer in animals and humans. Their effects may reflect the ability of the epoxide metabolites to stimulate the proliferation and survival of the target cancer cells but perhaps also to stimulate these cells to trigger new capillary formation (see
A series of drugs derived from Terfenadine have been shown to inhibit CYP2J2 and to suppress the proliferation and cause the apoptosis of various types of human cancer cell lines in culture as well as in animal models.[43] However, clinical studies targeting CYP epoxygenases and EETs and to successfully suppress cancer in humans have not been reported.
Pro-angiogenic and tumor promoting effects of EETs have been attributed to downstream cyclooxygenase (COX)-derived metabolites. Dual sEH/COX inhibitors or sEH inhibitors supplemented with an enhanced omega-3 fatty acid diet and a depleted omega-6 fatty acid diet have been shown to induce significant anti-angiogenic effects and blunt tumor growth.[45]
Inflammation
In vitro and animal model studies indicate that the EETs possess
Diabetes, non-alcoholic fatty liver disease, and kidney disease
EETs, pharmacological inhibition of sEH, and/or inhibition of sEH expression enhance insulin actions on animal tissues in vitro and have protective effects in ameliorating insulin resistance as well as many of the neurological and kidney complications of diabetes in various animal models of diabetes; the studies suggest that the EETs have beneficial effects in
Pain
EETs have been shown to have anti-hyperalgesic and pain-relieving activity in several animal models of pain including nociception resulting from tissue injury, inflammation, and peripheral neuropathy (see Neuropathic pain) including pain secondary to experimentally induced diabetes in mice.[13][48][46] The epoxides of omega-3 fatty acids appear far stronger and more involved in the relief of pain than the EETs (see Epoxydocosapentaenoic acid).[13]
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