Epoxyeicosatrienoic 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] The cytochrome P450 (CYP) superfamily of enzymes is distributed broadly throughout bacteria, archaea, fungi, plants, animals, and even viruses.
[9] CYP2S1 is expressed in macrophages, liver, lung, intestine, and spleen and is abundant in human and mouse atherosclerosis (i.e. atheroma) plaques as well as inflamed tonsils.
In animal models, 20-HETE raises blood pressure by contracting arteries and stimulating the kidney to reabsorb salt and water to increase the intravascular volume (see 20-Hydroxyeicosatetraenoic acid).
[23] These and large number of other studies included in the cited references implicate the EETs in the control of at least certain forms of hypertension in rodents.
[9] Finally, 11,12-EET has been shown to relax the internal mammary artery in women, indicating that at least this EET has direct vasodilating actions in humans.
[9] On the other hand, several studies in humans with single nucleotide polymorphism in CYP epxoygenase genes have given negative or confusing results.
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 contribute in small or large part to vasodilation responses and by this action promote blood flow to tissues and function in lowering high blood pressures.
Furthermore, the genetic studies conducted to date on SNP variants do not give strong support for an antihypertensive role for the EETs or EET-forming epoxygenases in humans.
[12] Testing for their usefulness in treating human hypertension is made difficult because of: 1) the large number of CYP epoxygenases along with their differing tissue distributions and sensitivities to drug inhibitors; 2) the diversity of EETs made by the CYP epoxygenases, some of which differ in activities; 3) the diversity of fatty acid substrates metabolized by the CYP epoxygenases some of which are converted to epoxides (e.g. the epoxide metabolites of linoleic, docosahexaenoic, eicosapentaenoic acids), which have different activities than the EETs or may even be overtly toxic to humans (see Coronaric acid); 4) the sEH-derived dihydroxy metabolites of the EETs some of which have potent vasodilating effects in the certain vascular networks in rodents and therefore potentially in humans; and 5) the non-specificity and side effects of the latter drugs.
[28][12][29] 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.
Indeed, studies on in vivo animal and in vitro animal and human cell model systems indicate that the ETEs reduce infarct (i.e. injured tissue) size, reduce cardiac arrhythmias, and improve the strength of left ventricle contraction immediately after blockade of coronary artery blood flow in animal models of ischemia-reperfusion injury; EETs also reduce the size of heart enlargement that occurs long after these experiment-induced injuries.
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.
Thus, sEH inhibitors and sEH-gene knockout have been shown to reduce the damage to brain that occurs in several different models of ischemic stroke; this protective effect appears due to a reduction in systemic blood pressure and maintenance of blood flow to ischemic areas of the brain by arteriole dilation as a presumed consequence of inhibiting the degradation of EETs (and/or other fatty acid epoxides).
Vascular contraction in the portal system is mediated by several agents: nitric oxide, carbon monoxide, prostacyclin I2, and endothelium-derived hyperpolarizing factors (EDHFs).
[36] Levels of EETs in the plasma and liver of patients with cirrhosis and portal hypertension are reportedly elevated compared to normal subjects.
Forced expression of CYP2J2 also enhanced, while forced inhibition of its expression (using Small interfering RNA) reduced, the survival, growth, and metastasis of MDA-MB-231 human breast carcinoma cells in the mouse model and likewise enhanced or reduced, respectively, the survival and growth of these cells in culture.
[43] 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.
[6][7][43][44] 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.
[45] In vitro and animal model studies indicate that the EETs possess anti-inflammatory activity that is directed toward reducing, resolving, and limiting the damage caused by inflammation.
