Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and 5-Hydroxyeicosatetraenoic acid: Difference between pages

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| verifiedrevid = 477224558

| ImageFile=5-HETE.png

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| PIN=(5''S'',6''E'',8''Z'',11''Z'',14''Z'')-5-Hydroxyicosa-6,8,11,14-tetraenoic acid

| OtherNames=5-HETE, 5(S)-HETE

| IUPHAR_ligand = 3390

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| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo=70608-72-9

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| UNII = 467RNW8T91

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| C=20 | H=32 | O=3

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'''5-Hydroxyeicosatetraenoic acid''' ('''5-HETE''', '''5(''S'')-HETE''', or '''5''S''-HETE''') is an [[eicosanoid]], i.e. a metabolite of [[arachidonic acid]]. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(''S'')-HETE to [[5-oxo-eicosatetraenoic acid]] (5-oxo-ETE), 5(''S''),15(''S'')-dihydroxyeicosatetraenoic acid (5(''S''),15(''S'')-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(''S'')-HETE).

5(''S'')-HETE, 5-oxo-ETE, 5(''S''),15(''S'')-diHETE, and 5-oxo-15(''S'')-HETE, while differing in potencies, share a common mechanism for activating cells and a common set of activities. They are therefore a family of structurally related metabolites. Animal studies and a limited set of human studies suggest that this family of metabolites serve as [[hormone]]-like [[autocrine signalling|autocrine]] and [[paracrine signalling]] agents that contribute to the up-regulation of acute [[inflammation|inflammatory]] and [[allergic]] responses. In this capacity, these metabolites may be members of the [[innate immune system]].

''[[In vitro]]'' studies suggest that 5(''S'')-HETE and/or other of its family members may also be active in promoting the growth of certain types of cancers, in simulating bone reabsorption, in signaling for the secretion of [[aldosterone]] and [[progesterone]], in triggering [[parturition]], and in contributing to other responses in animals and humans. However, the roles of 5(''S'')-HETE family members in these responses as well as in inflammation and allergy are unproven and will require much further study.

Among the 5(''S'')-HETE family members, 5(''S'')-HETE takes precedence over the other members of this family because it was the first to be discovered and has been studied far more thoroughly. However, 5-oxo-ETE is the most potent member of this family and therefore may be its critical member with respect to [[physiology]] and [[pathology]]. 5-OxoETE has gained attention in recent studies.

== Nomenclature ==

5-Hydroxyeicosatetraenoic acid is more properly termed 5(''S'')-hydroxyicosatetraenoic acid or 5(''S'')-HETE) to signify the (''S'') [[Chirality (chemistry)|configuration]] of its 5-[[hydroxyl|hydroxy]] residue as opposed to its 5(''R'')-hydroxyicosatetraenoic acid (i.e., 5(''R'')-HETE) [[stereoisomer]]. Since 5(''R'')-HETE was rarely considered in the early literature, 5(''S'')-HETE was frequently termed 5-HETE. This practice occasionally continues. 5(''S'')-HETE's [[IUPAC]] name, (5''S'',6''E'',8''Z'',11''Z'',14''Z'')-5-hydroxyicosa-6,8,11,14-tetraenoic acid, defines 5(''S'')-HETE's structure unambiguously by notating not only its ''S''-hydroxyl chirality but also the [[cis–trans isomerism]] geometry for each of its 4 [[double bond]]s; E signifies trans and Z signifies cis double bond geometry. The literature commonly uses an alternate but still unambiguous name for 5(''S'')-HETE viz., 5(''S'')-hydroxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid.

== History of discovery ==

The Nobel laureate, [[Bengt I. Samuelsson]], and colleagues first described 5(''S'')-HETE in 1976 as a metabolite of arachidonic acid made by rabbit [[neutrophil]]s.<ref>{{cite journal | vauthors = Borgeat P, Hamberg M, Samuelsson B | title = Transformation of arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases | journal = The Journal of Biological Chemistry | volume = 251 | issue = 24 | pages = 7816–20 | date = December 1976 | doi = 10.1016/S0021-9258(19)57008-9 | pmid = 826538 | doi-access = free }}</ref> Biological activity was linked to it several years later when it was found to stimulate human neutrophil rises in cytosolic calcium, [[chemotaxis]], and increases in their cell surface adhesiveness as indicated by their aggregation to each other.<ref name="pmid1668115">{{cite journal | vauthors = Rossi AG, O'Flaherty JT | title = Bioactions of 5-hydroxyicosatetraenoate and its interaction with platelet-activating factor | journal = Lipids | volume = 26 | issue = 12 | pages = 1184–8 | date = December 1991 | pmid = 1668115 | doi=10.1007/bf02536528| s2cid = 3964822 }}</ref> Since a previously discovered arachidonic acid metabolite made by neutrophils, [[leukotriene B4]] (LTB₄), also stimulates human neutrophil calcium rises, chemotaxis, and auto-aggregation and is structurally similar to 5(''S'')-HETE in being a 5(''S'')-hydroxy-eicosateraenoate, it was assumed that 5(''S'')-HETE stimulated cells through the same [[cell surface receptor]]s as those used by LTB₄ viz., the [[leukotriene B4 receptor]]s. However, further studies in neutrophils indicated that 5(''S'')-HETE acts through a receptor distinct from that used by LTB₄ as well as various other neutrophil stimuli. This 5(''S'')-HETE receptor is termed the [[oxoeicosanoid receptor 1]] (abbreviated as OXER1).<ref name="W Powell">{{cite journal | vauthors = O'Flaherty JT, Taylor JS, Thomas MJ | title = Receptors for the 5-oxo class of eicosanoids in neutrophils | journal = The Journal of Biological Chemistry | volume = 273 | issue = 49 | pages = 32535–41 | date = December 1998 | pmid = 9829988 | doi = 10.1074/jbc.273.49.32535 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Powell WS, Rokach J | title = Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE | journal = Progress in Lipid Research | volume = 44 | issue = 2–3 | pages = 154–83 | date = Mar 2005 | pmid = 15893379 | doi = 10.1016/j.plipres.2005.04.002 }}</ref>

== 5(''S'')-HETE production ==

5(''S'')-HETE is a product of the cellular metabolism of the n-6 [[polyunsaturated fatty acid]], arachidonic acid (i.e. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid), by [[ALOX5]] (also termed arachidonate-5-lipoxygenase, 5-lipoxygenase, 5-LO, and 5-LOX). ALOX5 metabolizes arachidonic acid to its [[hydroperoxide]] derivative, [[arachidonic acid 5-hydroperoxide]] i.e. 5(''S'')-hydroperoxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (5(''S'')-HpETE). 5(''S'')-HpETE may then be released and rapidly converted to 5(''S'')-HETE by ubiquitous cellular [[peroxidase]]s:

{{center|

Arachidonic acid + O₂ → 5(''S'')-HpETE → 5(''S'')-HETE}}

Alternatively, 5(''S'')-HpETE may be further metabolized to its [[epoxide]], 5(6)-oxido-eicosatetraenoic acid viz., [[leukotriene A4]] (i.e. 5''S'',6''S''-epoxy-7''E'',9''E'',11''Z'',14''Z''-eicosatetraenoic acid or 5''S''-5,6-oxido-7''E'',9''E'',11''Z'',14''Z''-eicosatetraenoic acid). Leukotriene A4 may then be further metabolized either to [[leukotriene B4]] by [[leukotriene A4 hydrolase]] or to [[leukotriene C4]] by [[leukotriene C4 synthase]]. Finally, leukotriene C4 may be metabolized to [[leukotriene D4]] and then to [[leukotriene E4]].<ref name="ReferenceC">{{cite journal | vauthors = Rådmark O, Werz O, Steinhilber D, Samuelsson B | title = 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 331–9 | date = April 2015 | pmid = 25152163 | doi = 10.1016/j.bbalip.2014.08.012 }}</ref> The relative amounts of these metabolites made by specific cells and tissues depends in large part on the relative content of the appropriate enzymes.

The selective synthesis of 5(''S'')-HETE (i.e. synthesis of 5(''S'')-HETE without concurrent synthesis of 5(''R'')-HETE) by cells is dependent on, and generally proportionate to, the presence and levels of its forming enzyme, ALOX5. Human ALOX5 is highly expressed in cells that regulate [[innate immunity]] responses, particularly those involved in [[inflammation]] and [[allergy]]. Examples of such cells include [[neutrophil]]s, [[eosinophil]]s, [[B lymphocyte]]s, [[monocyte]]s, [[macrophage]]s, [[mast cell]]s, [[dendritic cell]]s, and the monocyte-derived [[foam cell]]s of [[atherosclerosis]] tissues.<ref name="ReferenceC"/> ALOX5 is also expressed but usually at relatively low levels in many other cell types. The production of 5(''S'')-HETE by these cells typically serves a physiological function. However, ALOX5 can become overexpressed at high levels in certain types of human cancer cells such as those of the prostate, lung, colon, colorectal and pancreatic as a consequence of their [[malignant transformation]]. In these cells, the ALOX5-dependent production of 5(''S'')-HETE appears to serve a pathological function viz., it promotes the growth and spread of the cancer cells.<ref>{{cite journal | vauthors = Osher E, Weisinger G, Limor R, Tordjman K, Stern N | title = The 5 lipoxygenase system in the vasculature: emerging role in health and disease | journal = Molecular and Cellular Endocrinology | volume = 252 | issue = 1–2 | pages = 201–6 | date = June 2006 | pmid = 16647809 | doi = 10.1016/j.mce.2006.03.038 | s2cid = 17299214 }}</ref><ref name="pmid28125014">{{cite journal | vauthors = Moore GY, Pidgeon GP | title = Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway | journal = International Journal of Molecular Sciences | volume = 18 | issue = 2 | page = 236| year = 2017 | pmid = 28125014 | pmc = 5343774 | doi = 10.3390/ijms18020236 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bishayee K, Khuda-Bukhsh AR | title = 5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy | journal = Acta Biochimica et Biophysica Sinica | volume = 45 | issue = 9 | pages = 709–19 | date = September 2013 | pmid = 23752617 | doi = 10.1093/abbs/gmt064 | doi-access = free }}</ref><ref name="pmid22002716">{{cite journal | vauthors = Schneider C, Pozzi A | title = Cyclooxygenases and lipoxygenases in cancer | journal = Cancer and Metastasis Reviews | volume = 30 | issue = 3–4 | pages = 277–94 | year = 2011 | pmid = 22002716 | pmc = 3798028 | doi = 10.1007/s10555-011-9310-3 }}</ref>

5(''S'')-HETE may also be made in combination with 5(''R'')-HETE along with numerous other ''(S,R)''-hydroxy [[polyunsaturated fatty acid]]s as a consequence of the non-enzymatic oxidation reactions. Formation of these products can occur in any tissue subjected to [[oxidative stress]].<ref name="pmid24056189">{{cite journal | vauthors = Powell WS, Rokach J | title = The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor | journal = Progress in Lipid Research | volume = 52 | issue = 4 | pages = 651–65 | year = 2013 | pmid = 24056189 | doi = 10.1016/j.plipres.2013.09.001 | pmc=5710732}}</ref><ref name="pmid7258296">{{cite journal | vauthors = O'Flaherty JT, Thomas MJ, Lees CJ, McCall CE | title = Neutrophil-aggregating activity of monohydroxyeicosatetraenoic acids | journal = The American Journal of Pathology | volume = 104 | issue = 1 | pages = 55–62 | year = 1981 | pmid = 7258296 | pmc = 1903737 }}</ref>

== 5(''S'')-HETE metabolism ==

In addition to its intrinsic activity, 5(''S'')-ETE can serve as an intermediate that is converted to other bioactive products. Most importantly, [[5-Hydroxyeicosanoid dehydrogenase]] (i.e. 5-HEDH) converts the 5-hydroxy residue of 5(''S'')-HETE to a [[ketone]] residue to form [[5-oxo-eicosatetraenoic acid]] (i.e. 5-oxo-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoate, abbreviated as 5-oxo-ETE). 5-HEDH is a reversibly acting [[NADP+|NADP⁺]]/[[NADPH]]-dependent enzyme that catalyzes to following reaction:

{{center|

5(''S'')-HETE + [[NADP+|NADP⁺]] <math>\rightleftharpoons</math> 5-oxo-ETE + [[NADPH]]}}

5-HEDH acts bi-directionally: it preferentially oxygenates 5(''S'')-HETE to 5-oxo-ETE in the presence of excess NADH⁺ but preferentially reduces 5-oxo-ETE back to 5(''S'')-HETE in the presence of excess NADPH. Since cells typically maintain far higher levels of NADPH than NADP⁺, they usually make little or no 5-oxo-ETE. When undergoing [[oxidative stress]], however, cells contain higher levels of NADH⁺ than NADPH and make 5-oxo-ETE preferentially. Additionally, ''[[in vitro]]'' studies indicate that cells can transfer their 5(''S'')-HETE to cells that contain high levels of 5-NEDH and NADP⁺ and therefore convert the transferred 5(''S'')-HETE to 5-oxo-ETE. It is suggested that 5-oxo-ETE forms preferentially ''[[in vivo]]'' under conditions of [[oxidative stress]] or conditions where [[ALOX5]]-rich cells can transfer their 5(''S'')-HETE to cells epithelial, endothelial, dendritic, and certain (e.g. prostate, breast, and lung) cancer cells which display little or no ALOX5 activity but have high levels of 5-NEDH and NADP⁺. Since 5-oxo-ETE is 30- to 100-fold more potent than 5(''S'')-HETE, 5-HEDH main function may be to increase the biological impact of 5-HETE production.<ref name="Biochim Biophys Acta 2014"/>

Cells metabolize 5-(''S'')-HETE in other ways. They may use:<ref name="Biochim Biophys Acta 2014">{{cite journal | vauthors = Powell WS, Rokach J | title = Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 340–55 | date = April 2015 | pmid = 25449650 | pmc = 5710736 | doi = 10.1016/j.bbalip.2014.10.008 }}</ref><ref name="pmid1668115"/><ref>{{cite journal | vauthors = Serhan CN | title = Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 73 | issue = 3–4 | pages = 141–62 | year = 2005 | pmid = 16005201 | doi = 10.1016/j.plefa.2005.05.002 }}</ref><ref>{{cite journal | vauthors = Tejera N, Boeglin WE, Suzuki T, Schneider C | title = COX-2-dependent and -independent biosynthesis of dihydroxy-arachidonic acids in activated human leukocytes | journal = Journal of Lipid Research | volume = 53 | issue = 1 | pages = 87–94 | date = January 2012 | pmid = 22068350 | pmc = 3243484 | doi = 10.1194/jlr.M017822 |doi-access=free }}</ref><ref>{{cite journal | pmid = 25895638 | year = 2015 | last1 = Romano | first1 = M | title = Lipoxins and aspirin-triggered lipoxins in resolution of inflammation | journal = European Journal of Pharmacology | volume = 760 | pages = 49–63 | last2 = Cianci | first2 = E | last3 = Simiele | first3 = F | last4 = Recchiuti | first4 = A | doi = 10.1016/j.ejphar.2015.03.083 }}</ref>

*An [[acyltransferase]] to [[ester]]ify 5(''S'')-HETE into their membrane [[phospholipid]]s. This reaction may serve to storing 5(''S'')-HETE for its release during subsequent cell stimulation and/or alter the properties of cell membranes in functionally important ways.

*A [[cytochrome P450]], probably [[CYP4F3]], to metabolize 5(''S'')-HETE to 5(''S''),20-dihydroxy-eicosatetraenoate (5,20-diHETE). Since 5,20-diHETE is ~50- to 100-fold weaker than 5(''S'')-HETE in stimulating cells, this metabolism is proposed to represent a pathway for 5(''S'')-HETE inactivation.

*[[ALOX15]] to metabolize 5(''S'')-HETE to 5(''S''),15(''S'')-dihydroxy-eicosatetraenoate (5,15-diHETE). 5,15-diHETE is ~3- to 10-fold weaker than 5(''S'')-HETE in stimulating cells.

*12-Lipoxygenase (i.e. [[ALOX12]]) to metabolize 5(''S'')-HETE to 5(''S''),12(''S'')-diHETE. The activity of this product has not yet been fully evaluated.

*[[Cyclooxygenase-2]] to metabolize 5(''S'')-HETE to 5(''S''),15(''R'')-diHETE and 5(''S''),11(''R'')-diHETE. The activity of these products have not yet been fully evaluated.

*[[Aspirin]]-treated [[cyclooxygenase-2]] to metabolize 5(''S'')-HETE to 5(''S''),15(''R'')-diHETE. The activity of this product has not yet been fully evaluated.

Alternate pathways that make some of the above products include the: '''a)''' metabolism of 5(''S'')-HpETE to 5-oxo-ETE by [[cytochrome P450]] (CYP) enzymes such as [[CYP1A1]], [[CYP1A2]], [[CYP1B1]], and [[CYP2S1]]; '''b)''' conversion of 5-HETE to 5-oxo-ETE non-enzymatically by [[heme]] or other dehydrating agents; '''c)''' formation of 5-oxo-15(''S'')-hydroxy-ETE through 5-HEDH-based oxidation of 5(''S''),15(''S'')-dihydroxyicosatetraenoate; '''d)''' formation of 5(''S''),15(''R'')-dihydroxy-eicosatetraenoate by the attack of ALOX5 on [[15-hydroxyicosatetraenoic acid]] (15(''S'')-HETE); '''e)''' formation of 5-oxo-15(''S'')-hydroxy-eicosatetreaenoate (''5-oxo-15(''S'')-hydroxy-ETE'') by the arachidonate 15-lipoxygenase-1-based or arachidonate 15-lipoxygenase-2-based metabolism of 5-oxo-ETE; and '''f)''' conversion of 5(''S'')-HpETE and 5(''R'')-HpETE to 5-oxo-ETE by the action of a mouse [[macrophage]] 50-60 [[kilodalton]] cytosolic protein.<ref name="Biochim Biophys Acta 2014"/>

== Mechanism of action ==

=== The OXER1 receptor ===

5(''S'')-HETE family members share a common receptor target for stimulating cells that differs from the receptors targeted by the other major products of ALOX5, i.e., [[leukotriene B4]], [[leukotriene C4]], [[leukotriene D4]], [[leukotriene E4]], [[lipoxin]] A4, and [[lipoxin]] B4. It and other members of the 5(''S'')-HETE family stimulate cells primarily by binding and thereby activating a dedicated [[G protein-coupled receptor]], the [[oxoeicosanoid receptor 1]] (i.e. OXER1, also termed the OXE, OXE-R, hGPCR48, HGPCR48, or R527 receptor).<ref name="Biochim Biophys Acta 2014"/><ref name="ReferenceB">{{cite journal | vauthors = O'Flaherty JT, Rossi AG | title = 5-hydroxyicosatetraenoate stimulates neutrophils by a stereospecific, G protein-linked mechanism | journal = The Journal of Biological Chemistry | volume = 268 | issue = 20 | pages = 14708–14 | date = July 1993 | doi = 10.1016/S0021-9258(18)82391-2 | pmid = 8392058 | doi-access = free }}</ref> OXER1 couples to the [[G protein]] complex composed of the [[Gi alpha subunit]] (Gαi) and [[G beta-gamma complex]] (Gβγ); when bound to a 5-(''S'')-HETE family member, OXER1 triggers this G protein complex to dissociate into its Gαi and Gβγ components with Gβγ appearing to be the component responsible for activating the signal pathways which lead to cellular functional responses.<ref name="Biochim Biophys Acta 2014"/> The cell-activation pathways stimulated by OXER1 include those mobilizing calcium ions and activating [[MAPK/ERK]], [[p38 mitogen-activated protein kinases]], cytosolic [[phospholipase A2]], [[PI3K]]/[[Akt]], and [[protein kinase C]] beta and epsilon.<ref name="Biochim Biophys Acta 2014"/><ref name="Prog Lipid Res 2013. p 19">{{cite journal | vauthors = Powell WS, Rokach J | title = The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor | journal = Progress in Lipid Research | volume = 52 | issue = 4 | pages = 651–65 | date = October 2013 | pmid = 24056189 | doi = 10.1016/j.plipres.2013.09.001 | pmc=5710732}}</ref> The relative potencies of 5-oxo-ETE, 5-oxo-15(''S'')-HETE, 5(''S'')-HETE, 5(''S''),15(''S'')-diHETE, 5-oxo-20-hydroxy-ETE, 5(''S''),20-diHETE, and 5,15-dioxo-ETE in binding to, activating, and thereby stimulating cell responses through the OXER1 receptor are ~100, 30, 5-10, 1-3, 1-3, 1, and <1, respectively.<ref name="W Powell" /><ref name="Prog Lipid Res 2013. p 19"/><ref>{{cite journal | vauthors = O'Flaherty JT, Cordes JF, Lee SL, Samuel M, Thomas MJ | title = Chemical and biological characterization of oxo-eicosatetraenoic acids | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1201 | issue = 3 | pages = 505–15 | date = December 1994 | pmid = 7803484 | doi = 10.1016/0304-4165(94)90083-3 }}</ref>

=== Other receptors ===

Progress in proving the role of the 5-HETE family of agonists and their OXER1 receptor in human physiology and disease has been made difficult because mice, rats, and the other rodents so far tested lack OXER1. Rodents are the most common ''[[in vivo]]'' models for investigating these issues. OXER1 is expressed in non-human primates, a wide range of other mammals, and various fish species and a model of allergic airways disease in cats, which express OXER1 and make 5-oxo-ETE, has recently been developed for such studies.<ref name="Prog Lipid Res 2013. p 19"/><ref name="Biochem Pharmacol 2015"/> In any event, cultured mouse [[MA-10 cell|MA-10]] [[Leydig cell]]s, while responding to 5-oxo-ETE, lack OXER1. It is suggested that this cell's, as well as mouse and other rodent, responses to 5-oxo-ETE are mediated by a receptor closely related to OXER11 viz., the mouse [[niacin receptor 1]], Niacr1. Niacr1, an [[ortholog]] of OXER1, is a G protein-coupled receptor for [[Niacin (substance)|niacin]], and responds to 5-oxo-ETE.<ref name="doi10.1016/j.mce.2012.11.003"/> It has also been suggested that one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 ([[GPR81]]), HCA2 ([[GPR109A]]), and HCA3 ([[GPR109B]]), which are G protein-coupled receptors for fatty acids may be responsible for rodent responses to 5-oxo-ETE.<ref name="doi10.1016/j.mce.2012.11.003"/> It is possible that human cellular responses to 5-oxo-ETE and perhaps its analogs may involve, at least in isolated instances, one or more of these receptors.

=== PPARγ ===

5-Oxo-15(''S'')-hydroxy-ETE and to a lesser extent 5-oxo-ETE but not 5(''S'')-HETE also bind to and activate [[peroxisome proliferator-activated receptor gamma]] (PPARγ). Activation of OXER1 receptor and PPARγ by the oxo analogs can have opposing effects on cells. For example, 5-oxo-ETE-bound OXER1 stimulates while 5-oxo-ETE-bound PPARγ inhibits the proliferation of various types of human cancer cell lines.<ref name="Biochim. Biophys 2005">{{cite journal | vauthors = O'Flaherty JT, Rogers LC, Paumi CM, Hantgan RR, Thomas LR, Clay CE, High K, Chen YQ, Willingham MC, Smitherman PK, Kute TE, Rao A, Cramer SD, Morrow CS | title = 5-Oxo-ETE analogs and the proliferation of cancer cells | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1736 | issue = 3 | pages = 228–36 | date = October 2005 | pmid = 16154383 | doi = 10.1016/j.bbalip.2005.08.009 }}</ref>

=== Other mechanisms ===

5(''S'')-HETE acylated into the [[phosphatidylethanolamine]]s fraction of human neutrophil membranes is associated with the inhibition of these cells from forming [[neutrophil extracellular traps]], i.e. extracellular DNA scaffolds which contain neutrophil-derived antimicrobial proteins that circulate in blood and have the ability to trap bacteria. It seems unlikely that this inhibition reflects involvement of OXER1.<ref name="ReferenceA">{{cite journal | vauthors = Clark SR, Guy CJ, Scurr MJ, Taylor PR, Kift-Morgan AP, Hammond VJ, Thomas CP, Coles B, Roberts GW, Eberl M, Jones SA, Topley N, Kotecha S, O'Donnell VB | title = Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection | journal = Blood | volume = 117 | issue = 6 | pages = 2033–43 | date = February 2011 | pmid = 21177434 | pmc = 3374621 | doi = 10.1182/blood-2010-04-278887 }}</ref> 5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.<ref name="Prog Lipid Res 2013. p 19"/><ref name="pmid17499751"/>

== Clinical significance ==

=== Inflammation ===

5(''S'')-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils ([[Polymorphonuclear neutrophil|PMN]]), a leukocyte blood cell type involved in host immune defense against infection but also implicated in aberrant pro-inflammatory immune responses such as arthritis; soon thereafter they found to be active also in stimulating these cells to migrate (i.e. chemotaxis), degranulate (i.e. release the anti-bacterial and tissue-injuring contents of their granules), produce bacteriocidal and tissue-injuring [[reactive oxygen species]], and mount other pro-defensive as well as pro-inflammatory responses of the [[innate immune system]]. For example, the [[gram-negative bacterium]], ''[[Salmonella tryphimurium]]'', and the outer surface of gram-negative bacteria [[lipopolysaccharide]], promote the production of 5(''S'')-HETE and 5-oxo-ETE by human neutrophils. The family members stimulate another blood cell of the [[innate immunity]] system, the human [[monocyte]], acting synergistically with the pro-inflammatory [[CC chemokines]], [[monocyte chemotactic protein-1]] and monocyte chemotactic protein-3, to stimulate monocyte function. 5-Oxo-ETE also stimulates two other cell types that share responsibility with the PMN for regulating inflammation, the human [[lymphocyte]] and [[dendritic cell]]. And, ''in vivo'' studies, the injection of 5-oxo-ETE into the skin of human volunteers causes the local accumulation of PMN and monocyte-derived [[macrophage]]s.<ref name="Prog Lipid Res 2013. p 19"/> Furthermore, the production of one or more 5(''S'')-HETE family members as well as the expression of orthologs of the human OXER1 receptor occur in various mammalian species including dogs, cats, cows, sheep, elephants, pandas, opossums, and ferrets and in several species of fish; for example, cats undergoing experimentally induced asthma accumulate 5-oxo-ETE in their lung lavage fluid, feline leucocytes make as well as respond to 5-oxo-ETE by an oxer1-dependent mechanism; and an OXER1 ortholog and, apparently, 5-oxo-ETE are necessary for the inflammatory response to tissue damage caused by osmolarity insult in [[zebrafish]].<ref name="Biochim Biophys Acta 2014" /><ref>{{cite journal | vauthors = Enyedi B, Kala S, Nikolich-Zugich T, Niethammer P | title = Tissue damage detection by osmotic surveillance | journal = Nature Cell Biology | volume = 15 | issue = 9 | pages = 1123–30 | date = September 2013 | pmid = 23934216 | pmc = 3826879 | doi = 10.1038/ncb2818 }}</ref><ref name="Biochem Pharmacol 2015">{{cite journal | vauthors = Cossette C, Gravel S, Reddy CN, Gore V, Chourey S, Ye Q, Snyder NW, Mesaros CA, Blair IA, Lavoie JP, Reinero CR, Rokach J, Powell WS | title = Biosynthesis and actions of 5-oxoeicosatetraenoic acid (5-oxo-ETE) on feline granulocytes | journal = Biochemical Pharmacology | volume = 96 | issue = 3 | pages = 247–55 | date = August 2015 | pmid = 26032638 | pmc = 4830392 | doi = 10.1016/j.bcp.2015.05.009 }}</ref>

These results given above suggest that members of the 5-oxo-ETE family and the OXER1 receptor or its orthologs may contribute to protection against microbes, the repair of damaged tissues, and pathological inflammatory responses in humans and other animal species.<ref name="Biochim Biophys Acta 2014" /> However, an OXER1 ortholog is absent in mice and other rodents; while rodent tissues do exhibit responsiveness to 5-oxo-ETE, the lack of an oxer1 or other clear 5-oxoETE receptor in such valued animal models of diseases as rodents has impeded progress in our understanding of the physiological and pathological roles of 5-oxo-ETE.<ref name="Biochem Pharmacol 2015"/>

=== Allergy ===

The following human cell types or tissues that are implicated in allergic reactivity produce 5-HETE (stereoisomer typically not defined): alveolar macrophages isolated from asthmatic and non-asthmatic patients, [[basophil]]s isolated from blood and challenged with anti-IgE antibody, [[mast cell]]s isolated from lung, cultured pulmonary artery endothelial cells, isolated human pulmonary vasculature, and allergen-sensitized human lung specimens challenged with specific allergen.<ref name="Prog Lipid Res 2013. p 19"/><ref>{{cite journal | vauthors = Grant GE, Rokach J, Powell WS | title = 5-Oxo-ETE and the OXE receptor | journal = Prostaglandins & Other Lipid Mediators | volume = 89 | issue = 3–4 | pages = 98–104 | date = September 2009 | pmid = 19450703 | pmc = 2906239 | doi = 10.1016/j.prostaglandins.2009.05.002 }}</ref> Additionally, cultured human airway epithelial cell lines, normal bronchial epithelium, and bronchial smooth muscle cells convert 5(''S'')-HETE to 5-oxo-ETE in a reaction that is greatly increase by oxidative stress, which is a common component in allergic inflammatory reactions.<ref name="Prog Lipid Res 2013. p 19"/> Finally, 5-HETE is found in the [[bronchoalveolar lavage fluid]] of asthmatic humans and 5-oxo-ETE is found in the bronchoalveolar lavage fluid of cats undergoing allergen-induced bronchospasm.<ref name="Prog Lipid Res 2013. p 19"/><ref name="Biochem Pharmacol 2015"/><ref>{{cite journal | vauthors = Dworski R, Fitzgerald GA, Oates JA, Sheller JR | title = Effect of oral prednisone on airway inflammatory mediators in atopic asthma | journal = American Journal of Respiratory and Critical Care Medicine | volume = 149 | issue = 4 Pt 1 | pages = 953–9 | date = April 1994 | pmid = 8143061 | doi = 10.1164/ajrccm.149.4.8143061 }}</ref>

Among the 5-HETE family of metabolites, 5-oxo-ETE is implicated as the most likely member to contribute to allergic reactions. It has exceptionally high potency in stimulating the [[chemotaxis]], release of granule-bound tissue-injuring enzymes, and production of tissue-injuring reactive oxygen species of a cell type involved in allergic reactions, the human [[eosinophil granulocyte]].<ref name="Prog Lipid Res 2013. p 19"/> It is also exceptionally potent in stimulating eosinophils to activate cytosolic phospholipase A2 ([[PLA2G4A]]) and possibly thereby to form [[platelet-activating factor]] (PAF) as well as metabolites of the 5-HETE family.<ref name="Prog Lipid Res 2013. p 19"/><ref>{{cite journal | vauthors = O'Flaherty JT, Kuroki M, Nixon AB, Wijkander J, Yee E, Lee SL, Smitherman PK, Wykle RL, Daniel LW | title = 5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes | journal = Journal of Immunology | volume = 157 | issue = 1 | pages = 336–42 | date = July 1996 | doi = 10.4049/jimmunol.157.1.336 | pmid = 8683135 | s2cid = 35264541 | doi-access = free }}</ref> PAF is itself a proposed mediator of human allergic reactions which commonly forms concurrently with 5-HETE family metabolites in human leukocytes and acts synergistically with these metabolites, particularly 5-oxo-ETE, to stimulate eosinophils.<ref name="Prog Lipid Res 2013. p 19"/><ref>{{cite journal | vauthors = Chilton FH, O'Flaherty JT, Walsh CE, Thomas MJ, Wykle RL, DeChatelet LR, Waite BM | title = Platelet activating factor. Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine | journal = The Journal of Biological Chemistry | volume = 257 | issue = 10 | pages = 5402–7 | date = May 1982 | doi = 10.1016/S0021-9258(19)83790-0 | pmid = 6802816 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Swendsen CL, Ellis JM, Chilton FH, O'Flaherty JT, Wykle RL | title = 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine: a novel source of arachidonic acid in neutrophils stimulated by the calcium ionophore A23187 | journal = Biochemical and Biophysical Research Communications | volume = 113 | issue = 1 | pages = 72–9 | date = May 1983 | pmid = 6407484 | doi = 10.1016/0006-291x(83)90433-3 }}</ref><ref>{{cite journal | vauthors = Wijkander J, O'Flaherty JT, Nixon AB, Wykle RL | title = 5-Lipoxygenase products modulate the activity of the 85-kDa phospholipase A2 in human neutrophils | journal = The Journal of Biological Chemistry | volume = 270 | issue = 44 | pages = 26543–9 | date = November 1995 | pmid = 7592874 | doi = 10.1074/jbc.270.44.26543 | doi-access = free }}</ref> 5-Oxo-ETE also cooperates positively with at least four other potential contributors to allergic reactions, [[RANTES]], [[eotaxin]], [[granulocyte macrophage colony-stimulating factor]], and [[granulocyte colony-stimulating factor]] in stimulating human eosinophils and is a powerful stimulator of chemotaxis in another cell type contributing to allergic reactions, the human [[basophil granulocyte]].<ref name="Prog Lipid Res 2013. p 19"/> Finally, 5-oxo-ETE stimulates the infiltration of eosinophils into the skin of humans following its intradermal injection (its actions are more pronounced in asthmatic compared to healthy subjects) and when instilled into the trachea of Brown Norway rats causes eosinophils to infiltrate lung.<ref name="Prog Lipid Res 2013. p 19"/> These results suggest that the 5-oxo-ETE made at the initial tissue site of allergen insult acting through the OXER1 on target cells attracts circulating eosinophils and basophils to lung, nasal passages, skin, and possibly other sites of allergen deposition to contribute to asthma, rhinitis, and dermatitis, and other sites of allergic reactivity.<ref name="Prog Lipid Res 2013. p 19"/><ref>{{cite journal | vauthors = Rubin P, Mollison KW | title = Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids | journal = Prostaglandins & Other Lipid Mediators | volume = 83 | issue = 3 | pages = 188–97 | date = May 2007 | pmid = 17481554 | doi = 10.1016/j.prostaglandins.2007.01.005 }}</ref>

The role of 5-HETE family agonists in the [[bronchoconstriction]] of airways (a hallmark of allergen-induced asthma) in humans is currently unclear. 5-HETE stimulates the contraction of isolated human bronchial muscle, enhances the ability of histamine to contract this muscle, and contracts guinea pig lung strips.<ref>{{cite journal | vauthors = Copas JL, Borgeat P, Gardiner PJ | title = The actions of 5-, 12-, and 15-HETE on tracheobronchial smooth muscle | journal = Prostaglandins, Leukotrienes, and Medicine | volume = 8 | issue = 2 | pages = 105–14 | date = February 1982 | pmid = 6952280 | doi = 10.1016/s0262-1746(82)80002-4 }}</ref> 5-Oxo-ETE also stimulates contractile responses in fresh bronchi, cultured bronchi, and cultured lung smooth muscle taken from guinea pigs but in direct contrast to these studies is reported to relax bronchi isolated from humans.<ref name="pmid17499751">{{cite journal | vauthors = Morin C, Sirois M, Echave V, Gomes MM, Rousseau E | title = Relaxing effects of 5-oxo-ETE on human bronchi involve BK Ca channel activation | journal = Prostaglandins & Other Lipid Mediators | volume = 83 | issue = 4 | pages = 311–9 | date = June 2007 | pmid = 17499751 | doi = 10.1016/j.prostaglandins.2007.03.001 }}</ref><ref>{{cite journal | vauthors = Morin C, Rousseau E | title = Effects of 5-oxo-ETE and 14,15-EET on reactivity and Ca²⁺ sensitivity in guinea pig bronchi | journal = Prostaglandins & Other Lipid Mediators | volume = 82 | issue = 1–4 | pages = 30–41 | date = January 2007 | pmid = 17164130 | doi = 10.1016/j.prostaglandins.2006.05.012 }}</ref><ref>{{cite journal | vauthors = Mercier F, Morin C, Cloutier M, Proteau S, Rokach J, Powell WS, Rousseau E | title = 5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca²⁺ pools and Rho-kinase pathway | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 287 | issue = 4 | pages = L631–40 | date = October 2004 | pmid = 15090369 | doi = 10.1152/ajplung.00005.2004 | s2cid = 22972003 }}</ref> The latter bronchi contractile responses were blocked by cyclooxygenase-2 inhibition or a thromboxane A2 receptor antagonist and therefore appear mediated by 5-oxo-ETE-induced production of this thromboxane. In all events, the relaxing action of 5-oxo-ETE on human bronchi does not appear to involve OXER1.<ref name="Prog Lipid Res 2013. p 19"/>

=== Cancer ===

The 5-oxo-ETE family of agonists have also been proposed to contribute to the growth of several types of human cancers. This is based on their ability to stimulate certain cultured human cancer cell lines to proliferate, the presence of OXER1 mRNA and/or protein in these cell lines, the production of 5-oxo-ETE family members by these cell lines, the induction of cell death (i.e. apoptosis) by inhibiting 5-lipoxygenase in these cells, and/or the overexpression of 5-lipoxygenase in tissue taken from the human tumors. Human cancers whose growth has been implicated by these studies as being mediated at least in part by a member(s) of the 5-oxo-ETE family include those of the prostate, breast, lung, ovary, and pancreas.<ref name="Prog Lipid Res 2013. p 19"/><ref name="Biochim. Biophys 2005"/><ref>{{cite journal | vauthors = Avis IM, Jett M, Boyle T, Vos MD, Moody T, Treston AM, Martínez A, Mulshine JL | title = Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling | journal = The Journal of Clinical Investigation | volume = 97 | issue = 3 | pages = 806–13 | date = February 1996 | pmid = 8609238 | pmc = 507119 | doi = 10.1172/JCI118480 }}</ref><ref name="Oncology 65:285-294, 2003">{{cite journal | vauthors = Ding XZ, Tong WG, Adrian TE | title = Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer | journal = Oncology | volume = 65 | issue = 4 | pages = 285–94 | date = 2003 | pmid = 14707447 | doi = 10.1159/000074640 | s2cid = 22159108 }}</ref>

=== Steroid production ===

5(''S'')-HETE and 5(''S'')-HpETE stimulate the production of [[progesterone]] by cultured rat ovarian glomerulosa cells<ref>{{cite journal | vauthors = Wang J, Yuen BH, Leung PC | title = Stimulation of progesterone and prostaglandin E2 production by lipoxygenase metabolites of arachidonic acid | journal = FEBS Letters | volume = 244 | issue = 1 | pages = 154–8 | date = February 1989 | pmid = 2494061 | doi = 10.1016/0014-5793(89)81182-2 | s2cid = 42436005 | doi-access = free | bibcode = 1989FEBSL.244..154W }}</ref> and enhance the secretion of progesterone and [[testosterone]] by cultured rat testicular [[Leydig cell]]s.<ref>{{cite journal | vauthors = Reddy GP, Prasad M, Sailesh S, Kumar YV, Reddanna P | title = Arachidonic acid metabolites as intratesticular factors controlling androgen production | journal = International Journal of Andrology | volume = 16 | issue = 3 | pages = 227–33 | date = June 1993 | pmid = 8359939 | doi = 10.1111/j.1365-2605.1993.tb01184.x | doi-access = free }}</ref> Both metabolites are made by [[cyclic adenosine monophosphate]]-stimulated [[MA-10 cell|MA-10 mouse Leydig cell]]s; stimulate these cells to transcribe [[steroidogenic acute regulatory protein]], and in consequence produce the [[steroid]]s.<ref>{{cite journal | vauthors = Wang XJ, Dyson MT, Jo Y, Eubank DW, Stocco DM | title = Involvement of 5-lipoxygenase metabolites of arachidonic acid in cyclic AMP-stimulated steroidogenesis and steroidogenic acute regulatory protein gene expression | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 85 | issue = 2–5 | pages = 159–66 | date = June 2003 | pmid = 12943700 | doi = 10.1016/s0960-0760(03)00189-4 | s2cid = 36071655 }}</ref><ref>{{cite journal | vauthors = Wang X, Walsh LP, Reinhart AJ, Stocco DM | title = The role of arachidonic acid in steroidogenesis and steroidogenic acute regulatory (StAR) gene and protein expression | journal = The Journal of Biological Chemistry | volume = 275 | issue = 26 | pages = 20204–9 | date = June 2000 | pmid = 10777507 | doi = 10.1074/jbc.m003113200 | doi-access = free }}</ref> The results suggest that trophic hormones (e.g., [[leutenizing hormone]], [[adrenocorticotropic hormone]]) stimulate these steroid producing cells to make 5(''S'')-HETE and 5(''S'')-HpEPE which in turn increase the synthesis of steroidogenic acute regulatory protein; the latter protein promotes the rate-limiting step in steroidogenesis, transfer of cholesterol from the outer to the inner membrane of mitochondria and thereby acts in conjunction with trophic hormone-induce activation of protein kinase A to make progesterone and testosterone.<ref>{{cite journal | vauthors = Wang XJ, Dyson MT, Mondillo C, Patrignani Z, Pignataro O, Stocco DM | title = Interaction between arachidonic acid and cAMP signaling pathways enhances steroidogenesis and StAR gene expression in MA-10 Leydig tumor cells | journal = Molecular and Cellular Endocrinology | volume = 188 | issue = 1–2 | pages = 55–63 | date = February 2002 | pmid = 11911946 | doi = 10.1016/S0303-7207(01)00748-1 | hdl = 11336/36241 | s2cid = 30710602 | hdl-access = free }}</ref> This pathway may also operate in humans: Human [[H295R]] adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway.<ref name="doi10.1016/j.mce.2012.11.003">{{cite journal | vauthors = Cooke M, Di Cónsoli H, Maloberti P, Cornejo Maciel F | title = Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells | journal = Molecular and Cellular Endocrinology | volume = 371 | issue = 1–2 | pages = 71–8 | date = May 2013 | pmid = 23159987 | doi = 10.1016/j.mce.2012.11.003 | s2cid = 8520991 | hdl = 11336/8381 | hdl-access = free }}</ref>

Rat and mouse cells lack OXER1. It has been suggested that the cited [[MA-10 cell|mouse MA-10 cell]] responses to 5-oxo-ETE are mediated by an ortholog to OXER1, mouse [[niacin receptor 1]], Niacr1, which is a G protein-coupled receptor mediating the activity of [[Niacin (substance)|niacin]], or by one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 ([[GPR81]]), HCA2 ([[GPR109A]]), and HCA3 ([[GPR109B]]), which are G protein-coupled receptors for fatty acids.<ref name="doi10.1016/j.mce.2012.11.003" /> In any event, Human H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway.<ref name="doi10.1016/j.mce.2012.11.003" />

=== Bone remodeling ===

In an ''in vitro'' mixed culture system, 5(''S'')-HETE is released by monocytes to stimulate, at sub-nanomolar concentrations, osteoclast-dependent bone reabsorption.<ref>{{cite journal | vauthors = Gallwitz WE, Mundy GR, Lee CH, Qiao M, Roodman GD, Raftery M, Gaskell SJ, Bonewald LF | title = 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices | journal = The Journal of Biological Chemistry | volume = 268 | issue = 14 | pages = 10087–94 | date = May 1993 | doi = 10.1016/S0021-9258(18)82175-5 | pmid = 8486677 | doi-access = free }}</ref> It also inhibits morphogenetic protein-2 (BMP-2)-induced bone-like nodule formation in mouse calvarial organ cultures.<ref>{{cite journal | vauthors = Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF | title = 5-Lipoxygenase metabolites inhibit bone formation ''in vitro'' | journal = Endocrinology | volume = 139 | issue = 7 | pages = 3178–84 | date = July 1998 | pmid = 9645691 | doi = 10.1210/endo.139.7.6115 | doi-access = free }}</ref> These results allow that 5(''S'')-HETE and perhaps more potently, 5-oxo-ETE contribute to the regulation of [[bone remodeling]].

=== Parturition ===

5(''S'')-HETE is: elevated in the human uterus during [[parturition|labor]];<ref>{{cite journal | vauthors = Pearson T, Zhang J, Arya P, Warren AY, Ortori C, Fakis A, Khan RN, Barrett DA | title = Measurement of vasoactive metabolites (hydroxyeicosatetraenoic and epoxyeicosatrienoic acids) in uterine tissues of normal and compromised human pregnancy | journal = Journal of Hypertension | volume = 28 | issue = 12 | pages = 2429–37 | date = December 2010 | pmid = 20852449 | doi = 10.1097/HJH.0b013e32833e86aa | s2cid = 27983033 }}</ref> at 3–150 [[Molar concentration|nM]], increases both the rates of spontaneous contractions and overall contractility of myometrial strips obtained at term but prior to labor from human lower uterine segments;<ref>{{cite journal | vauthors = Bennett PR, Elder MG, Myatt L | title = The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility | journal = Prostaglandins | volume = 33 | issue = 6 | pages = 837–44 | date = June 1987 | pmid = 2823315 | doi = 10.1016/0090-6980(87)90112-2 }}</ref> and in an ''in vitro'' system crosses either [[amnion]] or intact amnion-chorion-decidua and thereby may along with [[prostaglandin E2]] move from the amnion to uterus during labor in humans.<ref>{{cite journal | vauthors = Bennett PR, Chamberlain GV, Patel L, Elder MG, Myatt L | title = Mechanisms of parturition: the transfer of prostaglandin E2 and 5-hydroxyeicosatetraenoic acid across fetal membranes | journal = American Journal of Obstetrics and Gynecology | volume = 162 | issue = 3 | pages = 683–7 | date = March 1990 | pmid = 2316568 | doi = 10.1016/0002-9378(90)90984-F }}</ref> These studies allow that 5(''S'')-HETE, perhaps in cooperation with established role of prostaglandin E2, may play a role in the onset of human labor.

=== Other actions ===

5(''S'')-HETE is reported to modulate [[tubuloglomerular feedback]].<ref>{{cite book|vauthors=Boron WF, Boulpaep EL|title=Medical physiology : a cellular and molecular approach|date=2005|publisher=Elsevier Saunders|location=Philadelphia, Pa.|isbn=978-1416023289|edition=Updated}}</ref> 5(''S'')-HpETE is also reported to inhibit the [[Sodium–potassium pump|{{chem2|Na+/K+}}-ATPase]] activity of [[synaptosome]] membrane preparations prepared from rat [[cerebral cortex]] and may thereby inhibit synapse-dependent communications between neurons.<ref>{{cite journal | vauthors = Foley TD | title = 5-HPETE is a potent inhibitor of neuronal Na⁺, K⁺-ATPase activity | journal = Biochemical and Biophysical Research Communications | volume = 235 | issue = 2 | pages = 374–6 | date = June 1997 | pmid = 9199200 | doi = 10.1006/bbrc.1997.6790 | url = https://zenodo.org/record/1229478 }}</ref>

5(''S'')-HETE acylated into phosphatidylethanolamine is reported to increase the stimulated production of [[superoxide anion]] and interleukin-8 release by isolated human neutrophils and to inhibit the formation of [[neutrophil extracellular traps]] (i.e. NETS); NETS trap blood-circulating bacteria to assist in their neutralization.<ref name="ReferenceA"/> 5(''S'')-HETE esterified to phosphatidylcholine and glycerol esters by human endothelial cells is reported to be associated with the inhibition of [[prostaglandin]] production.<ref>{{cite journal | vauthors = Richards CF, Johnson AR, Campbell WB | title = Specific incorporation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid into phosphatidylcholine in human endothelial cells | journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism | volume = 875 | issue = 3 | pages = 569–81 | date = February 1986 | pmid = 3004591 | doi=10.1016/0005-2760(86)90079-2}}</ref>

== See also ==

* [[Arachidonic acid]]

* [[5-Lipoxygenase]]

* [[5-Oxo-eicosatetraenoic acid]]

* [[Leukotriene B4]]

* [[Polyunsaturated fat]]

* [[12-Hydroxyeicosatetraenoic acid]]

* [[15-Hydroxyeicosatetraenoic acid]]

== References ==

{{Reflist|33em}}

== External links ==

*[http://atlasgeneticsoncology.org/Genes/GC_ALOX5.html 5-LOX Gene Atlas entry]

*[http://atlasgeneticsoncology.org//Genes/ALOX5ID42985ch10q11.html 5-LOX entry in Atlas of Genetics and Cytogenetics in Oncology and Haematology entry]

{{DEFAULTSORT:Hydroxyeicosatetraenoic acid, 5-HETE}}

[[Category:Human physiology]]

[[Category:Animal physiology]]

[[Category:Fatty acids]]

[[Category:Eicosanoids]]

[[Category:Immunology]]

[[Category:Inflammations]]

[[Category:Cell signaling]]