20-hydroxyeicosatetraenoic acid

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of 20-hydroxyeicosatetraenoic acid
General
Surname (5 Z , 8 Z , 11 Z , 14 Z ) -20-Hydroxyeicosa-5,8,11,14-tetraenoic acid
other names
  • 20-hydroxyeicosatetraenoic acid
  • 20-HETE
Molecular formula C 20 H 32 O 3
External identifiers / databases
CAS number 79551-86-3
PubChem 5283157
ChemSpider 4446281
Wikidata Q21099666
properties
Molar mass 320.47 g mol −1
safety instructions
GHS labeling of hazardous substances
02 - Highly / extremely flammable 07 - Warning

danger

H and P phrases H: 225-319
P: 210-305 + 351 + 338-370 + 378-403 + 235
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

20-Hydroxyeicosatetraenoic acid , also known as 20-HETE , is a metabolite of arachidonic acid with a broad spectrum of activity, especially on the cardiovascular system and the kidneys . In a physiological way, 20-HETE is involved in the regulation of blood pressure and organ blood flow. Preclinical studies suggest a role for 20-HETE in the pathogenesis of heart attacks and strokes. A loss of the synthetic ability of 20-HETE is associated with the occurrence of hereditary spastic paraplegia (HSP). Overproduction of 20-HETE can contribute to the development of tumors, especially breast cancer .

biosynthesis

Production in humans

20-HETE is synthesized from arachidonic acid by cytochrome P450- ω-hydroxylases (CYP450). In most tissues, the subtypes CYP4A and CYP4F are responsible for this reaction. These enzymes also produce the related 19-HETE in small quantities. In addition, the subtypes CYP2U1 and CYP4F8 are able to convert the two forms into one another. However, depending on the tissue, the amount of enzymes used differs considerably.

The enantiomer 19 ( R ) -HETE is able to antagonize the effects of 20-HETE on the cardiovascular system.

Many of the enzymes involved are also able to hydroxylate shorter or longer chain fatty acids. They are therefore also important for the formation of various prostaglandins and leukotrienes which, together with 20-HETE, can induce and modulate inflammatory processes.

Production in rodents and other animals

In mice, 19-HETE and 20-HETE are synthesized by the two related enzymes CYP4A12A and CYP4A12B; the isoform CYP4A12A is androgen-dependently active in the male kidney. In rats, the enzymes CYP4A1, CYP4A2, CYP4A3 and CYP4A8 are responsible for this. However, the distribution of the enzymes in the individual tissues differs greatly from that in humans, so that comparative studies are difficult.

The enzymes CYP2J9 (in mice), CYP2J3 (in rats) and CYP2J (in sheep) metabolize arachidonic acid primarily to 19-HETE. The cytochromes of the CYP2J type can also form 18-HETE.

Regulation of biosynthesis

The biosynthesis of 20-HETE can be increased by a number of factors. Androgens , angiotensin II , endothelins and norepinephrine should be emphasized here . From a pharmacological point of view , when COX-2 inhibitors such as NSAIDs , opioids and furosemide are given , it should be noted that they can increase the biosynthesis of 20-HETE.

Biosynthesis is inhibited by nitrogen monoxide , carbon monoxide and superoxide anions. These physiological inhibitors act by binding to the heme in the cytochromes. On the pharmacological side, the 20-HETE synthesis can be inhibited by arachidonic acid analogues.

Dissemination of the enzymes

20-HETE-forming enzymes are very common in humans in the liver, kidneys, brain, lungs and intestines. In blood vessels, the activity is limited to the vascular smooth muscles, while the endothelium produces almost no 20-HETE. In addition, 20-HETE can be produced by blood cells such as neutrophils and platelets .

metabolism

The most important way to break down 20-HETE is conjugation with activated glucuronic acid as part of biotransformation. In addition, many other degradation pathways are known, some of which in turn produce biologically active metabolites such as prostaglandins and leukotrienes.

Effects in rodents

Narrowing of blood vessels

In various rodent models it could be shown that 20-HETE can constrict arteries in low concentrations (below 50 nmol / l). This mechanism works by sensitizing the smooth muscle cells to vasoconstricting substances such as alpha-adrenergic agonists, vasopressin, endothelin and angiotensin II.

20-HETE interacts with the RAAS in a complex manner: Angiotensin II stimulates the production of 20-HETE in the preglomerular capillaries of the kidney. This production is required so that angiotensin II can develop its full vasoconstrictor effect. 20-HETE also induces angiotensin converting enzyme (ACE) transcription . Other substances such as androgens and norepinephrine also stimulate 20-HETE production and have vasoconstrictor effects that are intensified by 20-HETE.

In another mouse model, 20-HETE was able to block calcium-dependent potassium channels. This promotes the influx of calcium into smooth muscle cells through L-type Ca 2+ channels, which increases muscle contraction and thus vasoconstriction.

In rats it could be shown that 20-HETE inhibits the association of NO synthase (eNOS) with the chaperone Hsp90 in endothelial cells . This means that the eNOS cannot be activated. The cells cannot synthesize vasodilating NO and potentially harmful superoxide anions can accumulate in the cytosol.

20-HETE can also constrict arteries directly by activating the thromboxane A 2 receptor (more on this in the section on vascular tone ).

These vasoconstrictor effects can decrease blood flow in specific parts of the body. With systemic effects, 20-HETE can increase blood pressure.

Injury to blood vessels

Rats in which the common carotid artery was selectively damaged subsequently showed increased activity of CYP4A and, as a result, increased levels of 20-HETE in the affected tissue. The inhibition of the 20-HETE-producing enzymes could significantly reduce the intimal proliferation and the restructuring of the vascular structure on the damaged endothelium. These effects suggest that 20-HETE is physiologically involved in the healing of vascular injuries.

Thrombosis

In the C57BL / 6 mouse model, it was shown that 20-HETE can accelerate the development of thromboses in the common carotid and femoral arteries, thereby reducing blood flow through the affected vessels. Studies on human cells from umbilical veins show that 20-HETE can act as an extracellular activator of kinase cascades that increase the release of the thrombosis-promoting Von Willebrand factor .

Renal absorption

In animal models, 20-HETE can activate protein kinase C (PKC) in the epithelial cells of the renal tubule. The activated PKC phosphorylates and inhibits sodium-potassium-ATPase and also blocks the sodium-potassium-chloride symporter (NKCC) and a potassium channel in the ascending loop of Henle . This reduces the absorption of sodium and water in the nephron and thus lowers the blood pressure.

high blood pressure

As described above, 20-HETE can both increase and decrease blood pressure. The effects of 20-HETE are complex, as the following animal model studies show. Many of the models seem to produce effects similar to those in humans. For example, men are more likely to have high blood pressure than women; however, this ratio changes when considering postmenopausal women with relatively higher androgen levels.

Spontaneous high blood pressure

Spontaneously hypertensive rats show elevated levels of CYTP4A2 and 20-HETE. When the 20-HETE production was blocked, the blood pressure could be significantly reduced, especially in female animals after menopause.

Salt-sensitive high blood pressure

Salt-sensitive rats very quickly develop arterial hypertension with high salt intake, which can be treated very well by reducing salt consumption. In this model, rats show an upregulated CYP4A / 20-HETE metabolism in the cerebral vasculature and an increased production of reactive oxygen species (ROS) in the endothelial cells, which in turn stimulate the CYP4A / 20-HETE metabolism. The inhibition of CYP4A and 20-HETE production can lower blood pressure. The hypertension in this model is more common in male rats and appears to be influenced by vasopressin and the RAAS .

In another model, it could be shown that the effect of 20-HETE on blood pressure depends not only on the affected organ, but also on the individual areas of an organ: While an inhibitor does not reduce 20-HETE production in the renal cortex and the blood pressure rose as a result, the same inhibitor worked in the renal medulla.

Androgen-induced hypertension

The administration of androgens causes high blood pressure in male and female rats. This increase in pressure can be significantly reduced by inhibitors of CYP4A and other 20-HETE-synthesizing enzymes.

Genetically engineered high blood pressure

Transgenic mice overexpressing CYP4A12 develop androgen-independent hypertension, which is associated with increased levels of 20-HETE. This can be completely treated by a CYP4A-selective inhibitor. Male mice that do not express CYP4A14 as a result of gene knockout develop androgen-dependent hypertension. This apparently paradoxical result can be explained by the reactive overexpression of CYP4A12A. The knockout of CYP4A14, which does not produce 20-HETE, leads to increased expression of the 20-HETE-producing CYP4A149 and consequent overproduction of 20-HETE. In this experiment it was also possible to obtain evidence that the increased blood pressure is caused, among other things, by the increased incorporation of the sodium proton antiport 3 in the kidneys. Results from the CYP4A12 transgenic mice support this thesis.

Mice without CYP4A10 have normal blood pressures on a low-salt diet, but high blood pressure with normal or increased salt consumption. This effect is due to a renal deficiency of CYP2C44 as a result of the loss of CYP4A10. CYP2C44 metabolizes arachidonic acid to a number of substances with a vasodilatory effect. The increased blood pressure can be effectively treated by activating CYP2C44.

Effects in humans

Genetic Studies

CYP4A11 polymorphism

The amino acid sequence of human CYP4A11 largely corresponds to two cytochromes in mice. It can therefore be assumed that the function in humans is at least similar. For example, a defect in human CYP4A11 causes high blood pressure, just like a defect in murine CYP4A14.

In a variant of the CYP4A11 gene, a thymidine has been replaced by a cytosine in place of 8590. This leads to an amino acid exchange in the protein that reduces the enzyme activity of CYP4A11 in relation to the production of 20-HETE, which has been linked to arterial hypertension. A mutation in the promoter region of CYTP4A11, which is associated with reduced transcription, is also associated with high blood pressure. In addition, an increased risk of strokes could be demonstrated with another mutation.

CYP4F2 polymorphism

A mutation was also detected in CYP4F2, which is associated with reduced 20-HETE synthesis activity and, especially in men, with increased blood pressure. An increased rate of strokes and heart attacks could also be demonstrated. A mutation in an intron has also been linked to high blood pressure.

CYP2U1 mutations

A mutation (c.947A> T) in CYP2U1 could be associated with the occurrence of hereditary spastic paraplegia (HSP) in a small group of patients. The mutation causes an amino acid exchange in the active center of the enzyme (Asp> Val). The amino acid exchange can lead to dysfunction of the mitochondria . Another mutation in CYP2U1 (c.1A> C / p.Met1?) Is found in less than one percent of HSP patients. Although the role of 20-HETE in these mutations has not been proven, the reduced production of 20-HETE and the associated decreased activation of the TRPV1 receptor in nerve tissue could contribute to the disease.

cancer

Breast cancer

Two human breast cancer cell lines were genetically engineered to overexpress CYP4Z1 and VEGF . The increased synthesis of CYP4Z1 also increased the production of 20-HETE. When these cells are transplanted into a mouse model, there is a marked increase in tumor growth compared to normal 20-HETE levels. When isoliquiritigenin, a drug used to treat cancer that can induce apoptosis , was administered, it was shown, among other effects, that the production of 20-HETE decreased. Adding 20-HETE to these cells can prevent apoptosis. Isoliquiritigenin can also inhibit the metastasis of tumors. This mechanism is also based on a reduction in 20-HETE production. The vascularization of the tumor tissue induced by VEGF and other substances can also be reduced by inhibiting the 20-HETE synthesis.

In the 3′-untranslated area of the mRNAs of CYP4Z1 and the pseudogene CYP4Z2P there are many identical miRNA binding sites. The translation of CYP4Z1 can be inhibited by binding specific miRNAs. When CYP4Z2P is expressed, the miRNAs bind to this mRNA and CYP4Z1 and thus 20-HETE can be formed again. In addition, the miRNAs in breast cancer cells stimulate the production of VEGF and thus the vascularization of the tumor tissue via the MAPK / ERK signaling pathway.

The cytochromes CYP4Z2, CYP4A11, CYP4A22, CYP4F2 and CYP4F3 are increasingly expressed in breast cancer tissue. Since these enzymes synthesize 20-HETE, there appears to be a link between 20-HETE production and the occurrence of breast cancer.

Other cancers

20-HETE stimulates the growth of human gliomas . When these cells are genetically engineered to overexpress CYP4Z1, the rate of synthesis of 20-HETE increases, which leads to rapid growth. This effect can be prevented by inhibiting the production of 20-HETE. Similar effects were found in non-small cell lung cancer . A selective inhibitor of 20-HETE production and an antagonist of 20-HETE were able to reduce the growth of kidney tumors in two cell lines.

In ovarian, colon, thyroid and lung cancer, increased expression of the mRNA of CYP4A11, CYP4A22, CYP4F2 and / or CYP4F3 was detected. This is associated with an increased level of CYP4F2 and thus the increased synthesis of 20-HETE from arachidonic acid. Ovarian carcinomas also express increased mRNA for CYP4Z1, which is associated with a poor prognosis.

While these studies suggest that CYP4A11, CYP4A22, CYP4F2 and / or CYP4F3 produce 20-HETE, which in turn promotes the growth of these cancers in model systems and can therefore also do this in human cancers, this finding clearly requires further investigation. For example, an inhibitor of 20-HETE production blocks the growth of glioma cells of the human brain in culture. However, since these cells could not be shown to produce 20-HETE, it is believed that another metabolite is responsible for maintaining cell growth. Previously unknown side effects of the inhibitor could also be responsible for these effects.

Platelet aggregation

20-HETE inhibits the aggregation of platelets through direct competition for the enzymes that convert arachidonic acid into prostaglandins and leukotrienes (competitive inhibitor). In addition, the platelets metabolize 20-HETE to 20-hydroxyl analogs of prostaglandin H2 and thromboxane A2, which are almost completely inactive but inhibit the synthesis of the actual arachidonic acid derivatives. Furthermore, 20-HETE blocks the receptors for thromboxane A2 competitively, so that here too only a reduced effect can occur. These three effects ensure the anti-aggregation effect of 20-HETE. In order for this effect to take full effect, however, concentrations are required that are far above the physiological levels. Therefore these effects are more of a pharmacological nature.

Vascular tone

20-HETE can directly constrict arterioles by binding to the thromboxane A 2 receptor. It was also possible to demonstrate that the production of 20-HETE can be induced by increased blood flow. Therefore, it is believed that 20-HETE plays a role in the autoregulation of blood flow, which is particularly pronounced in the kidneys and brain.

Metabolic syndrome

A study with 30 people suffering from metabolic syndrome showed significantly increased plasma and urine levels of 20-HETE compared to the control group.

additional

It could be shown in mice and humans that 20-HETE can activate the cation channel TRPV1 ( transient receptor potential , subfamily V, subtype 1 or vanilloid receptor 1). This is related to pain and heat perception.

Individual evidence

  1. ↑ a b Data sheet 20- Hydroxy- (5Z, 8Z, 11Z, 14Z) - eicosatetraenoic acid, ~ 100 μg / mL in ethanol, ≥90% (HPLC) Template: Linktext-Check / Escaped from Sigma-Aldrich , accessed on August 17, 2018 ( PDF ).
  2. ↑ a b c Kroetz DL, Xu F: Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation . In: Annual Review of Pharmacology and Toxicology . 45, 2005, pp. 413-38. doi : 10.1146 / annurev.pharmtox.45.120403.100045 . PMID 15822183 .
  3. ↑ SS Chuang, C Helvig, M Taimi, HA Ramshaw, AH Collop, M Amad, JA White, M Petkovich, G Jones, B Korczak: CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and ( omega-1) hydroxylation of fatty acids . In: Journal of Biological Chemistry . 279, No. 8, 2004, pp. 6305-14. doi : 10.1074 / jbc.M311830200 . PMID 14660610 .
  4. ↑ JP Hardwick: Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases . In: Biochemical Pharmacology . 75, No. 12, 2008, pp. 2263-75. doi : 10.1016 / j.bcp.2008.03.004 . PMID 18433732 .
  5. ↑ J. Cheng, JS Ou, H Singh, JR Falck, D Narsimhaswamy, KA Pritchard Jr, ML Schwartzman: 20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling . In: AJP: Heart and Circulatory Physiology . 294, No. 2, 2008, pp. H1018-26. doi : 10.1152 / ajpheart.01172.2007 . PMID 18156192 .
  6. ↑ a b c d J. H. Capdevila, W Wang, JR Falck: Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological / pathophysiological relevance . In: Prostaglandins & Other Lipid Mediators . 120, 2015, pp. 40-9. doi : 10.1016 / j.prostaglandins.2015.05.004 . PMID 25986599 . PMC 4575609 (free full text).
  7. ↑ a b c d Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC: Vascular actions of 20-HETE . In: Prostaglandins & Other Lipid Mediators . 120, July 2015, pp. 9-16. doi : 10.1016 / j.prostaglandins.2015.03.002 . PMID 25813407 . PMC 4575602 (free full text).
  8. ^ CC Wu, T Gupta, V Garcia, Y Ding, ML Schwartzman: 20-HETE and blood pressure regulation: Clinical implications . In: Cardiology in Review . 22, No. 1, 2014, pp. 1-12. doi : 10.1097 / CRD.0b013e3182961659 . PMID 23584425 . PMC 4292790 (free full text).
  9. ↑ a b c d C. C. Wu, ML Schwartzman: The role of 20-HETE in androgen-mediated hypertension . In: Prostaglandins & Other Lipid Mediators . 96, No. 1-4, 2011, pp. 45-53. doi : 10.1016 / j.prostaglandins.2011.06.006 . PMID 21722750 . PMC 3248593 (free full text).
  10. ↑ a b V Garcia, J Cheng, A Weidenhammer, Y Ding, CC Wu, F Zhang, K Gotlinger, JR Falck, ML Schwartzman: Androgen-induced hypertension in angiotensinogen deficient mice: Role of 20-HETE and EETS . In: Prostaglandins & Other Lipid Mediators . 116–117, 2015, pp. 124–30. doi : 10.1016 / j.prostaglandins.2014.12.001 . PMID 25526688 . PMC 4385421 (free full text).
  11. ↑ a b c N Miyata, RJ Roman: Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in vascular system . In: Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi . 41, No. 4, 2005, pp. 175-93. doi : 10.1540 / jsmr.41.175 . PMID 16258232 .
  12. ^ A b F Fan, Y Muroya, RJ Roman: Cytochrome P450 eicosanoids in hypertension and renal disease . In: Current Opinion in Nephrology and Hypertension . 24, No. 1, 2015, pp. 37-46. doi : 10.1097 / MNH.0000000000000088 . PMID 25427230 . PMC 4260681 (free full text).
  13. ↑ KM Knights, A Rowland, JO Miners: Renal drug metabolism in humans: The potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) . In: British Journal of Clinical Pharmacology . 76, No. 4, 2013, pp. 587-602. doi : 10.1111 / bcp.12086 . PMID 23362865 . PMC 3791982 (free full text).
  14. ↑ KZ Edson, AE Rettie: CYP4 enzymes as potential drug targets: Focus on enzyme multiplicity, inducers and inhibitors, and therapeutic modulation of 20-hydroxyeicosatetraenoic acid (20-HETE) synthase and fatty acid ω-hydroxylase activities . In: Current Topics in Medicinal Chemistry . 13, No. 12, 2013, pp. 1429-40. doi : 10.2174 / 15680266113139990110 . PMID 23688133 . PMC 4245146 (free full text).
  15. ↑ DL Kroetz, F Xu: Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation . In: Annual Review of Pharmacology and Toxicology . 45, 2005, pp. 413-38. doi : 10.1146 / annurev.pharmtox.45.120403.100045 . PMID 15822183 .
  16. ↑ Hill E, Murphy RC: Quantitation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) produced by human polymorphonuclear leukocytes using electron capture ionization gas chromatography / mass spectrometry . In: Biological Mass Spectrometry . 21, No. 5, May 1992, pp. 249-53. doi : 10.1002 / bms.1200210505 . PMID 1525186 .
  17. ↑ Tsai IJ, Croft KD, Puddey IB, Beilin LJ, Barden A: 20-Hydroxyeicosatetraenoic acid synthesis is increased in human neutrophils and platelets by angiotensin II and endothelin-1 . In: American Journal of Physiology. Heart and Circulatory Physiology . 300, No. 4, April 2011, pp. H1194-200. doi : 10.1152 / ajpheart.00733.2010 . PMID 21239640 .
  18. ↑ YB Jarrar, EY Cha, KA Seo, JL Ghim, HJ Kim, DH Kim, SJ Lee, JG Shin: Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation . In: The Journal of Lipid Research . 55, No. 11, 2014, pp. 2334–42. doi : 10.1194 / jlr.M051169 . PMID 25249502 . PMC 4617135 (free full text).
  19. ↑ F Zhang, MH Wang, JS Wang, B Zand, VR Gopal, JR Falck, M Laniado-Schwartzman, A Nasjletti: Transfection of CYP4A1 cDNA decreases diameter and increases responsiveness of gracilis muscle arterioles to constrictor stimuli . In: AJP: Heart and Circulatory Physiology . 287, No. 3, 2004, pp. H1089-95. doi : 10.1152 / ajpheart.00627.2003 . PMID 15130884 .
  20. ↑ J Kaide, F Zhang, Y Wei, Wang W, PR Gopal, JR Falck, M Laniado-Schwartzman, A Nasjletti: Vascular CO counter balances the sensitizing influence of 20-HETE on agonist-induced vasoconstriction . In: Hypertension . 44, No. 2, 2004, pp. 210-6. doi : 10.1161 / 01.HYP.0000135658.57547.bb . PMID 15226275 .
  21. ↑ a b c K. Z. Edson, AE Rettie: CYP4 enzymes as potential drug targets: Focus on enzyme multiplicity, inducers and inhibitors, and therapeutic modulation of 20-hydroxyeicosatetraenoic acid (20-HETE) synthase and fatty acid ω-hydroxylase activities . In: Current Topics in Medicinal Chemistry . 13, No. 12, 2013, pp. 1429-40. doi : 10.2174 / 15680266113139990110 . PMID 23688133 . PMC 4245146 (free full text).
  22. ↑ J Cheng, JS Ou, H Singh, JR Falck, D Narsimhaswamy, KA Pritchard Jr, ML Schwartzman: 20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling . In: AJP: Heart and Circulatory Physiology . 294, No. 2, 2008, pp. H1018-26. doi : 10.1152 / ajpheart.01172.2007 . PMID 18156192 .
  23. ↑ Wiest EF, Walsh-Wilcox MT, Rothe M, Schunck WH, Walker MK: Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-dioxin . In: Toxicological Sciences: an Official Journal of the Society of Toxicology . 154, No. 1, 2016, pp. 43–54. doi : 10.1093 / toxsci / kfw145 . PMID 27492226 . PMC 5091366 (free full text).
  24. ↑ a b Toth P, Rozsa B, Springo Z, Doczi T, Koller A: Isolated human and rat cerebral arteries constrict to increases in flow: role of 20-HETE and TP receptors . In: Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism . 31, No. 10, 2011, pp. 2096-105. doi : 10.1038 / jcbfm.2011.74 . PMID 21610722 . PMC 3208155 (free full text).
  25. ↑ a b Capra V, Bäck M, Angiolillo DJ, Cattaneo M, Sakariassen KS: Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation . In: Journal of Thrombosis and Haemostasis: JTH . 12, No. 2, 2014, pp. 126–37. doi : 10.1111 / jth.12472 . PMID 24298905 .
  26. ↑ LD Orozco, H Liu, E Perkins, DA Johnson, BB Chen, F Fan, RC Baker, RJ Roman: 20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries . In: Journal of Pharmacology and Experimental Therapeutics . 346, No. 1, 2013, pp. 67-74. doi : 10.1124 / jpet.113.203844 . PMID 23658377 . PMC 3684845 (free full text).
  27. ↑ J Wang, H Li, J He, B Li, Q Bao, X Zhang, Z Lv, Y Zhang, J Han, D Ai, Y Zhu: 20-Hydroxyeicosatetraenoic acid involved in endothelial activation and thrombosis . In: American Journal of Physiology. Heart and Circulatory Physiology . 308, No. 11, 2015, pp. H1359-67. doi : 10.1152 / ajpheart.00802.2014 . PMID 25820395 .
  28. ^ F Fan, Y Muroya, RJ Roman: Cytochrome P450 eicosanoids in hypertension and renal disease . In: Current Opinion in Nephrology and Hypertension . 24, No. 1, 2015, pp. 37-46. doi : 10.1097 / MNH.0000000000000088 . PMID 25427230 . PMC 4260681 (free full text).
  29. ↑ LL Yanes, R Lima, M Moulana, DG Romero, K Yuan, MJ Ryan, R Baker, H Zhang, F Fan, DD Davis, RJ Roman, JF Reckelhoff: Postmenopausal hypertension: Role of 20-HETE . In: AJP: Regulatory, Integrative and Comparative Physiology . 300, No. 6, 2011, pp. R1543-8. doi : 10.1152 / ajpregu.00387.2010 . PMID 21474427 . PMC 3119152 (free full text).
  30. ^ R Lima, LL Yanes, DD Davis, JF Reckelhoff: Roles played by 20-HETE, angiotensin II and endothelin in mediating the hypertension in aging female spontaneously hypertensive rats . In: AJP: Regulatory, Integrative and Comparative Physiology . 304, No. 3, 2013, pp. R248-51. doi : 10.1152 / ajpregu.00380.2012 . PMID 23220478 . PMC 3567350 (free full text).
  31. ↑ KM Lukaszewicz, JH Lombard: Role of the CYP4A / 20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat . In: Clinical Science . 124, No. 12, 2013, pp. 695-700. doi : 10.1042 / CS20120483 . PMID 23438293 . PMC 4106241 (free full text).
  32. ↑ JT Crofton, M Ota, L Share: Role of vasopressin, the renin-angiotensin system and sex in Dahl salt-sensitive hypertension . In: Journal of Hypertension . 11, No. 10, 1993, pp. 1031-8. doi : 10.1097 / 00004872-199310000-00005 . PMID 8258666 .
  33. ↑ LL Yanes, JC Sartori-Valinotti, R Iliescu, DG Romero, LC Racusen, H Zhang, JF Reckelhoff: Testosterone-dependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats . In: AJP: Renal Physiology . 296, No. 4, 2009, pp. F771-9. doi : 10.1152 / ajprenal.90389.2008 . PMID 19211690 . PMC 2670635 (free full text).
  34. ^ DE Stec, DL Mattson, RJ Roman: Inhibition of renal outer medullary 20-HETE production produces hypertension in Lewis rats . In: Hypertension . 29, No. 1 Pt 2, 1997, pp. 315-9. doi : 10.1161 / 01.HYP.29.1.315 . PMID 9039121 .
  35. Jump up ↑ CC Wu, S. Mei, J. Cheng, Y. Ding, A. Weidenhammer, V. Garcia, F. Zhang, K. Gotlinger, VL Manthati, JR Falck, JH Capdevila, ML Schwartzman: Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20-HETE synthase . In: Journal of the American Society of Nephrology . 24, No. 8, 2013, pp. 1288-96. doi : 10.1681 / ASN.2012070714 . PMID 23641057 . PMC 3736709 (free full text).
  36. ↑ VR Holla, F Adas, JD Imig, X Zhao, E Price Jr, N Olsen, WJ Kovacs, MA Magnuson, DS Keeney, MD Breyer, JR Falck, MR Waterman, JH Capdevila: Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension . In: Proceedings of the National Academy of Sciences . 98, No. 9, 2001, pp. 5211-6. bibcode : 2001PNAS ... 98.5211H . doi : 10.1073 / pnas.081627898 . PMID 11320253 . PMC 33189 (free full text).
  37. ↑ R Quigley, S Chakravarty, X Zhao, JD Imig, JH Capdevila: Increased renal proximal convoluted tubule transport contributes to hypertension in Cyp4a14 knockout mice . In: Nephron Physiology . 113, No. 4, 2009, pp. 23-8. doi : 10.1159 / 000235774 . PMID 19713718 . PMC 2790762 (free full text).
  38. ^ P Fidelis, L Wilson, K Thomas, M Villalobos, AO Oyekan: Renal function and vasomotor activity in mice lacking the Cyp4a14 gene . In: Experimental Biology and Medicine . 235, No. 11, 2010, pp. 1365-74. doi : 10.1258 / ebm.2010.009233 . PMID 20943934 .
  39. ↑ K Nakagawa, VR Holla, Y Wei, WH Wang, A Gatica, S Wei, S Mei, CM Miller, DR Cha, E Price Jr, R Zent, ​​A Pozzi, MD Breyer, Y Guan, JR Falck, MR Waterman, JH Capdevila: Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel . In: Journal of Clinical Investigation . 116, No. 6, 2006, pp. 1696-702. doi : 10.1172 / JCI27546 . PMID 16691295 . PMC 1459070 (free full text).
  40. ↑ S Imaoka, H Ogawa, S Kimura, FJ Gonzalez: Complete cDNA sequence and cDNA-directed expression of CYP4A11, a fatty acid omega-hydroxylase expressed in human kidney . In: DNA and cell biology . 12, No. 10, 1993, pp. 893-9. doi : 10.1089 / dna.1993.12.893 . PMID 8274222 .
  41. ↑ JV Gainer, A Bellamine, EP Dawson, KE Womble, SW Grant, Y Wang, LA Cupples, CY Guo, S Demissie, CJ O'Donnell, NJ Brown, MR Waterman, JH Capdevila: Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension . In: Circulation . 111, No. 1, 2005, pp. 63-9. doi : 10.1161 / 01.CIR.0000151309.82473.59 . PMID 15611369 .
  42. ↑ JV Gainer, MS Lipkowitz, C Yu, MR Waterman, EP Dawson, JH Capdevila, NJ Brown, Group Aask Study: Association of a CYP4A11 variant and blood pressure in black men . In: Journal of the American Society of Nephrology . 19, No. 8, 2008, pp. 1606-12. doi : 10.1681 / ASN.2008010063 . PMID 18385420 . PMC 2488260 (free full text).
  43. ↑ Z Fu, T Nakayama, N Sato, Y Izumi, Y Kasamaki, A Shindo, M Ohta, M Soma, N Aoi, M Sato, Y Ozawa, Y Ma: A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men . In: Journal of Hypertension . 26, No. 3, 2008, pp. 453-61. doi : 10.1097 / HJH.0b013e3282f2f10c . PMID 18300855 .
  44. ↑ K Sugimoto, H Akasaka, T Katsuya, K Node, T Fujisawa, I Shimaoka, O Yasuda, M Ohishi, T Ogihara, K Shimamoto, H Rakugi: A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population . In: Hypertension . 52, No. 6, 2008, pp. 1142-8. doi : 10.1161 / HYPERTENSIONAHA.108.114082 . PMID 18936345 .
  45. ↑ H Ding, G Cui, L Zhang, Y Xu, X Bao, Y Tu, B Wu, Q Wang, R Hui, W Wang, RT Dackor, GE Kissling, DC Zeldin, DW Wang: Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population . In: Pharmacogenetics and Genomics . 20, No. 3, 2010, pp. 187-94. doi : 10.1097 / FPC.0b013e328336eefe . PMID 20130494 . PMC 3932492 (free full text).
  46. ↑ DE Stec, RJ Roman, A Flasch, MJ Rieder: Functional polymorphism in human CYP4F2 decreases 20-HETE production . In: Physiological Genomics . 30, No. 1, 2007, pp. 74-81. doi : 10.1152 / physiolgenomics.00003.2007 . PMID 17341693 .
  47. ↑ C Fava, M Ricci, O Melander, P Minuz: Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation? . In: Prostaglandins & Other Lipid Mediators . 98, No. 3-4, 2012, pp. 75-85. doi : 10.1016 / j.prostaglandins.2011.11.007 . PMID 22173545 .
  48. ↑ a b A Munshi, V Sharma, S Kaul, A Al-Hazzani, AA Alshatwi, G Shafi, R Koppula, SB Mallemoggala, A Jyothy: Association of 1347 G / A cytochrome P450 4F2 (CYP4F2) gene variant with hypertension and stroke . In: Molecular Biology Reports . 39, No. 2, 2012, pp. 1677-82. doi : 10.1007 / s11033-011-0907-y . PMID 21625857 .
  49. ↑ Z Fu, T Nakayama, N Sato, Y Izumi, Y Kasamaki, A Shindo, M Ohta, M Soma, N Aoi, M Sato, K Matsumoto, Y Ozawa, Y Ma: A haplotype of the CYP4F2 gene is associated with cerebral infarction in Japanese men . In: American Journal of Hypertension . 21, No. 11, 2008, pp. 1216-23. doi : 10.1038 / ajh.2008.276 . PMID 18787519 .
  50. ↑ a b C Tesson, M Nawara, MA Salih, R Rossignol, MS Zaki, M Al Balwi, R Schule, C Mignot, E Obre, A Bouhouche, FM Santorelli, CM Durand, AC Oteyza, KH El-Hachimi, A Al Drees, N Bouslam, F Lamari, SA Elmalik, MM Kabiraj, MZ Seidahmed, T Esteves, M Gaussen, ML Monin, G Gyapay, D Lechner, M Gonzalez, C Depienne, F Mochel, J Lavie, L Schols: Alteration of fatty -acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia . In: The American Journal of Human Genetics . 91, No. 6, 2012, pp. 1051-64. doi : 10.1016 / j.ajhg.2012.11.001 . PMID 23176821 . PMC 3516610 (free full text).
  51. ↑ SB Wortmann, M Espeel, L Almeida, A Reimer, D Bosboom, F Roels, AP De Brouwer, RA Wevers: Inborn errors of metabolism in the biosynthesis and remodeling of phospholipids . In: Journal of Inherited Metabolic Disease . 38, No. 1, 2015, pp. 99–110. doi : 10.1007 / s10545-014-9759-7 . PMID 25178427 .
  52. ↑ A Citterio, A Arnoldi, E Panzeri, MG d'Angelo, M Filosto, R Dilena, F Arrigoni, M Castelli, C Maghini, C Germiniasi, F Menni, A Martinuzzi, N Bresolin, MT Bassi: Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis . In: Journal of Neurology . 261, No. 2, 2014, pp. 373-81. doi : 10.1007 / s00415-013-7206-6 . PMID 24337409 .
  53. ↑ W Yu, H Chai, Y Li, H Zhao, X Xie, H Zheng, C Wang, X Wang, G Yang, X Cai, JR Falck, J Yang: Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer . In: Toxicology and Applied Pharmacology . 264, No. 1, 2012, pp. 73-83. doi : 10.1016 / j.taap.2012.07.019 . PMID 22841774 . PMC 3439529 (free full text).
  54. ↑ Y Li, H Zhao, Y Wang, H Zheng, W Yu, H Chai, J Zhang, JR Falck, AM Guo, J Yue, R Peng, J Yang: Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K / Akt in human breast cancer . In: Toxicology and Applied Pharmacology . 272, No. 1, 2013, pp. 37-48. doi : 10.1016 / j.taap.2013.05.031 . PMID 23747687 .
  55. ↑ a b H Zheng, Y Li, Y Wang, H Zhao, J Zhang, H Chai, T Tang, J Yue, AM Guo, J Yang: Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion . In: Toxicology and Applied Pharmacology . 280, No. 1, 2014, pp. 10-20. doi : 10.1016 / j.taap.2014.07.018 . PMID 25094029 .
  56. ↑ TF Borin, DA Zuccari, BV Jardim-Perassi, LC Ferreira, AS Iskander, NR Varma, A Shankar, AM Guo, G Scicli, AS Arbab: HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice . In: PLoS ONE . 9, No. 12, 2014, p. E116247. bibcode : 2014PLoSO ... 9k6247B . doi : 10.1371 / journal.pone.0116247 . PMID 25549350 . PMC 4280215 (free full text).
  57. ↑ a b L Zheng, X Li, Y Gu, X Lv, T Xi: The 3'UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1 . In: Breast Cancer Research and Treatment . 150, No. 1, 2015, pp. 105-18. doi : 10.1007 / s10549-015-3298-2 . PMID 25701119 .
  58. ↑ M Cizkova, G Cizeron-Clairac, S Vacher, A Susini, C Andrieu, R Lidereau, I Bièche: Gene expression profiling reveals new aspects of PIK3CA mutation in ERalpha-positive breast cancer: Major implication of the Wnt signaling pathway . In: PLoS ONE . 5, No. 12, 2010, p. E15647. bibcode : 2010PLoSO ... 515647C . doi : 10.1371 / journal.pone.0015647 . PMID 21209903 . PMC 3012715 (free full text).
  59. ↑ a b A Alexanian, B Miller, RJ Roman, A Sorokin: 20-HETE-producing enzymes are up-regulated in human cancers . In: Cancer genomics & proteomics . 9, No. 4, 2012, pp. 163-9. PMID 22798501 . PMC 3601443 (free full text).
  60. ↑ W Yu, L Chen, YQ Yang, JR Falck, AM Guo, Y Li, J Yang: Cytochrome P450 ω-hydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer . In: Cancer Chemotherapy and Pharmacology . 68, No. 3, 2011, pp. 619-29. doi : 10.1007 / s00280-010-1521-8 . PMID 21120482 . PMC 3839420 (free full text).
  61. ↑ A Alexanian, VA Rufanova, B Miller, A Flasch, RJ Roman, A Sorokin: Down-regulation of 20-HETE synthesis and signaling inhibits renal adenocarcinoma cell proliferation and tumor growth . In: Anticancer Research . 29, No. 10, 2009, pp. 3819-24. PMID 19846914 . PMC 2807614 (free full text).
  62. ↑ A Alexanian, A Sorokin: Targeting 20-HETE producing enzymes in cancer - rationale, pharmacology, and clinical potential . In: OncoTargets and Therapy . 6, 2013, pp. 243-55. doi : 10.2147 / OTT.S31586 . PMID 23569388 . PMC 3615879 (free full text).
  63. ↑ GI Murray, S Patimalla, KN Stewart, ID Miller, SD Heys: Profiling the expression of cytochrome P450 in breast cancer . In: Histopathology . 57, No. 2, 2010, pp. 202-11. doi : 10.1111 / j.1365-2559.2010.03606.x . PMID 20716162 .
  64. ^ D Downie, MC McFadyen, PH Rooney, ME Cruickshank, DE Parkin, ID Miller, C Telfer, WT Melvin, GI Murray: Profiling cytochrome P450 expression in ovarian cancer: Identification of prognostic markers . In: Clinical Cancer Research . 11, No. 20, 2005, pp. 7369-75. doi : 10.1158 / 1078-0432.CCR-05-0466 . PMID 16243809 .
  65. ↑ MA Rieger, R Ebner, DR Bell, A Kiessling, J Rohayem, M Schmitz, A Temme, EP Rieber, B Weigle: Identification of a novel mammary-restricted cytochrome P450, CYP4Z1, with overexpression in breast carcinoma . In: Cancer Research . 64, No. 7, 2004, pp. 2357-64. doi : 10.1158 / 0008-5472.can-03-0849 . PMID 15059886 .
  66. ^ M Guo, RJ Roman, JR Falck, PA Edwards, AG Scicli: Human U251 glioma cell proliferation is suppressed by HET0016 N-hydroxy-N '- (4-butyl-2-methylphenyl) formamidine, a selective inhibitor of CYP4A . In: Journal of Pharmacology and Experimental Therapeutics . 315, No. 2, 2005, pp. 526-33. doi : 10.1124 / jpet.105.088567 . PMID 16081682 .
  67. ↑ NC Ward, IJ Tsai, A Barden, FM Van Bockxmeer, IB Puddey, JM Hodgson, KD Croft: A single nucleotide polymorphism in the CYP4F2 but not CYP4A11 gene is associated with increased 20-HETE excretion and blood pressure . In: Hypertension . 51, No. 5, 2008, pp. 1393-8. doi : 10.1161 / HYPERTENSIONAHA.107.104463 . PMID 18391101 .
  68. ↑ IJ Tsai, KD Croft, TA Mori, JR Falck, LJ Beilin, IB Puddey, AE Barden: 20-HETE and F2-isoprostanes in the metabolic syndrome: The effect of weight reduction . In: Free Radical Biology and Medicine . 46, No. 2, 2009, pp. 263-70. doi : 10.1016 / j.freeradbiomed.2008.10.028 . PMID 19013235 .
  69. ↑ H. Wen, J. Östman, KJ Bubb, C. Panayiotou, JV Priestley, MD Baker, A. Ahluwalia: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a novel activator of transient receptor potential vanilloid 1 (TRPV1) channel . In: Journal of Biological Chemistry . 287, No. 17, 2012, pp. 13868-76. doi : 10.1074 / jbc.M111.334896 . PMID 22389490 . PMC 3340178 (free full text).