Additionally the loss of its production appears to be one cause of the human neurological disease, hereditary spastic paraplegia.

[2] Among this superfamily, certain members of the CYP4A and CYP4F subfamilies in the CYP4 family are considered predominant cytochrome P450 enzymes that are responsible in most tissues for forming 20-HETE and, concurrently, smaller amounts of 19-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (19-HETE).

[8] Finally, CYP2U1, the only member of the human CYP2U subfamily, is highly expressed in brain and thymus and to lesser extents in numerous other tissues such as kidney, lung and heart.

[15] In mice, the only 20-HETE- and 19-HETE-producing enzymes of the Cyp4a subfamily are two extensively homologous ones, Cyp4a12a and Cyp4a12b; Cyp4a12a is expressed in the male kidney in an androgen hormone-dependent manner.

[18][19] Other stimulators include the powerful vasoconstriction-inducing agents, angiotensin II, endothelins, and alpha adrenergic compounds (e.g.

[21] Drugs that are substrates for the UDP-glucuronosyltransferase (UGT) enzymes which metabolize 20-HETE such as non-steroidal anti-inflammatory agents, opioids, gemfibrozil, Lasix, propanol, and various COX-2 inhibitors may act as perhaps unwanted side effects to increase the levels of 20-HETE.

[10][26][27] While many of the effects and diseases associated with the over- or under-expression, pharmacological inhibition, and single nucleotide or mutant variants of the cytochrome ω-hydroxylases have been attributed to their impact on 20-HETE production, the influence of these alternate metabolic actions have frequently not been defined.

[9] Coronary artery endothelial cells isolated from pigs incorporate 20-HETE primarily into the sn-2 position of phospholipids through a coenzyme A-dependent process.

[30] 20-HETE is produced by human neutrophils[38] and platelets[39] and by the ascending tubule cells in the medulla as well the pre-glomerular arterioles and certain other localized areas of the rabbit kidney.

[9][40] In various rodent models, 20-HETE, at low concentrations (<50 nanomolar), acts to constrict arteries by sensitizing (i.e. increasing) the contraction responses of these artery's smooth muscle cells to other contracting agents such as alpha adrenergic agonists,[41] vasopressin,[42] endothelin,[7] and a product of renin angiotensin system, angiotensin II.

The endothelial cells become dysfunctional in exhibiting decreased ability to produce the vasodilating agent, nitric oxide, and in containing elevated levels of a potentially injurious oxygen radical, superoxide anion; the blood vessels to which these dysfunctional endothelial cells belong are less able to dilate in response to the vasodilator, acetylcholine.

While significantly less potent than thromboxane A2 in activating this receptor, studies on rat and human cerebral artery preparations indicate that increased blood flow through these arteries triggers production of 20-HETE which in turn binds to thromboxane receptors to constrict these vessels and thereby reduce their blood blow.

The studies suggest that the increase in expression of CYP4A and production of 20-HETE contribute to vascular intima growth, remolding, and thereby healing of injured rat carotid arteries.

[46] In the C57BL/6 mouse laboratory model, 20-HETE pretreatment accelerates the development of thrombosis and reduces blood flow caused by the thrombosis-inducing agent, ferric chloride, in the common carotid and femoral arteries; companion studies on human umbilical vein endothelial cells indicate that 20-HETE stimulates the activation of extracellular signal-regulated kinases to cause ERK-dependent and L-type calcium channel-dependent release of von Willebrand factor which in turn stimulates the adhesion of platelets to the endothelial cells.

In animal models, 20-HETE stimulates the activation of protein kinase C in the epithelial cells of the proximal tubules of the kidney; the kinase then phosphorylates and thereby inhibits the Na+/K+-ATPase and concurrently also blocks the Na-K-Cl cotransporter and 70 pS K+ channel in the thick Ascending limb of loop of Henle (TALH); these effects reduce the absorption of sodium and fluids in the nephron and thereby tend to reduce blood pressure.

[18] Spontaneously hypertensive rats exhibit elevated levels of CYP4A2 and 20-HETE; blockade of 20-HETE production lowers blood pressure in this model.

[50] The hypertension in this model is more severe in male rats and appears to be mediated at least in part by vasopressin, the renin-angiotensin system, and androgens.

The model involves increased plasma androgens, increased vascular and urinary levels of 20-HETE, relief of hypertension by castration, and hypertension which is driven by excessive fluid reabsorption in the kidney's proximal tubule secondary to the overexpression of Sodium–hydrogen antiporter 3; these effects are presumed but not yet shown to be due to the overproduction of 20-HETE.

The gene polymorphism rs1126742 variant of CYP4A11 switches thymidine to cytosine at nucleotide 8590 [T8590C] and leads to a phenylalanine-to-serine substitution at amino acid 434); this F434S variant has significantly reduced ability to ω-oxidize arachidonic acid to 20-HETE and has been associated with essential hypertension in: 512 white males from Tennessee (Odds ratio=2.31); 1538 males and females from the Framingham Heart Study (Odds ratio=1.23);[61] males but not females in 732 black Americans with hypertensive renal disease participating in the African American Study of Kidney Disease;[62] males in a sample of 507 individuals in Japan[63] and in the third MONICA (MONitoring trends and determinants In Cardiovascular disease survey of 1397 individuals the homozygous C8590C genotype to the homozygous T8590T genotype with odds ratios of 3.31 for all subjects, 4.30 for males 2.93 for women);[64] A study of 1501 participants recruited from the Tanno-Sobetsu Study found that the variant -845G in the promoter region of CYP411 (−845A is the predominant genotype) is associated with reduced transcription of CYP411 as well as with hypertension (odds ratio of homozygous and heterozygous -845G genotype versus homozygous -845A was 1.42);[65] A haplotype tagging single-nucleotide polymorphism (SNP) (see Tag SNP) variant of CYP4A11, C296T (cytosine to thymine at position 296), was associated with a significantly increased risk of ischemic stroke (adjusted odds ratio of 1.50 in comparing homozygous and heterozygous C296T subjects to homozygous C286C subjects) in >2000 individuals taken from the Han Chinese population.

[76] A mutation (c.947A>T) in CYP2U1 has been associated with a small number of patients with Hereditary spastic paraplegia in that it segregates with the disease at the homozygous state in two afflicted families.

[79] While the role of 20-HETE in these mutations has not been established, the reduction in 20-HETE production and thereby 20-HETE's activation of the TRPV1 receptor in nerve tissues, it is hypothesized, may contribute to the disease.

[80][81] Isoliquiritigenin also inhibits the in vivo lung metastasis of MDA-MB-231 cell transplants while concurrently decreasing the tumor's levels of 20-HETE.

[81] The growth of MDA-MB-231 cells implanted into athymic nude female mice as well as the cells' production of a large variety of agents stimulating vascularization including vascular endothelial growth factor were inhibited by treating the mice with an inhibitor of 20-HETE production.

Since these miRNA's reduce the translation of CYP4Z1, the expression of CYP4Z2P can bind these miRNAs to reduce their interference with CYP4Z1 and thereby increase the production of CYP4Z1 protein and perhaps 20-HETE; indeed, force expression of these 3'UTRs promoted in vitro tumor angiogenesis in breast cancer cells partly via miRNA-dependent activation of the phosphoinositide 3-kinase-MAPK/ERK pathway and thereby stimulating the production of vascular endothelium growth factor and possibly other endothelium growth factors.

20-HETE inhibits the aggregation of human platelets by competing with arachidonic acid for the enzymes that produce prostaglandin H2 and thromboxane A2.

While significantly less potent than thromboxane A2 in activating this receptor, studies on human cerebral artery preparations indicate that increased blood flow through these arteries triggers production of 20-HETE which in turn binds to thromboxane receptors to constrict these vessels and thereby reduce their blood blow.