5-Hydroxyeicosatetraenoic acid

Last updated
5-Hydroxyeicosatetraenoic acid
5-HETE.png
Names
Preferred IUPAC name
(5S,6E,8Z,11Z,14Z)-5-Hydroxyicosa-6,8,11,14-tetraenoic acid
Other names
5-HETE, 5(S)-HETE
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.161.309 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C20H32O3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-16-19(21)17-15-18-20(22)23/h6-7,9-10,12-14,16,19,21H,2-5,8,11,15,17-18H2,1H3,(H,22,23)/b7-6-,10-9-,13-12-,16-14+/t19-/m1/s1 Yes check.svgY
    Key: KGIJOOYOSFUGPC-JGKLHWIESA-N Yes check.svgY
  • InChI=1/C20H32O3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-16-19(21)17-15-18-20(22)23/h6-7,9-10,12-14,16,19,21H,2-5,8,11,15,17-18H2,1H3,(H,22,23)/b7-6-,10-9-,13-12-,16-14+/t19-/m1/s1
    Key: KGIJOOYOSFUGPC-JGKLHWIEBQ
  • CCCCC/C=C\C/C=C\C/C=C\C=C\[C@H](CCCC(=O)O)O
  • O=C(O)CCC[C@H](O)/C=C/C=C\C\C=C/C\C=C/CCCCC
Properties
C20H32O3
Molar mass 320.473 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-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).

Contents

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 and paracrine signalling agents that contribute to the up-regulation of acute 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) configuration of its 5-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, (5S,6E,8Z,11Z,14Z)-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 bonds; 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-6E,8Z,11Z,14Z-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 neutrophils. [1] 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. [2] 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 receptors as those used by LTB4 viz., the leukotriene B4 receptors. 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). [3] [4]

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. 5Z,8Z,11Z,14Z-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-6E,8Z,11Z,14Z-eicosatetraenoic acid (5(S)-HpETE). 5(S)-HpETE may then be released and rapidly converted to 5(S)-HETE by ubiquitous cellular peroxidases:

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. 5S,6S-epoxy-7E,9E,11Z,14Z-eicosatetraenoic acid or 5S-5,6-oxido-7E,9E,11Z,14Z-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. [5] 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 neutrophils, eosinophils, B lymphocytes, monocytes, macrophages, mast cells, dendritic cells, and the monocyte-derived foam cells of atherosclerosis tissues. [5] 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. [6] [7] [8] [9]

5(S)-HETE may also be made in combination with 5(R)-HETE along with numerous other (S,R)-hydroxy polyunsaturated fatty acids as a consequence of the non-enzymatic oxidation reactions. Formation of these products can occur in any tissue subjected to oxidative stress. [10] [11]

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-6E,8Z,11Z,14Z-eicosatetraenoate, abbreviated as 5-oxo-ETE). 5-HEDH is a reversibly acting NADP+/NADPH-dependent enzyme that catalyzes to following reaction:

5(S)-HETE + NADP+ 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. [12]

Cells metabolize 5-(S)-HETE in other ways. They may use: [12] [2] [13] [14] [15]

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. [12]

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). [12] [16] 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. [12] 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. [12] [17] 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. [3] [17] [18]

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. [17] [19] In any event, cultured mouse MA-10 Leydig cells, 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, and responds to 5-oxo-ETE. [20] 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. [20] 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. [21]

Other mechanisms

5(S)-HETE acylated into the phosphatidylethanolamines 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. [22] 5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined. [17] [23]

Clinical significance

Inflammation

5(S)-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils (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 macrophages. [17] 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. [12] [24] [19]

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. [12] 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. [19]

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, basophils isolated from blood and challenged with anti-IgE antibody, mast cells isolated from lung, cultured pulmonary artery endothelial cells, isolated human pulmonary vasculature, and allergen-sensitized human lung specimens challenged with specific allergen. [17] [25] 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. [17] 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. [17] [19] [26]

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. [17] 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. [17] [27] 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. [17] [28] [29] [30] 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. [17] 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. [17] 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. [17] [31]

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. [32] 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. [23] [33] [34] 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. [17]

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. [17] [21] [35] [36]

Steroid production

5(S)-HETE and 5(S)-HpETE stimulate the production of progesterone by cultured rat ovarian glomerulosa cells [37] and enhance the secretion of progesterone and testosterone by cultured rat testicular Leydig cells. [38] Both metabolites are made by cyclic adenosine monophosphate-stimulated MA-10 mouse Leydig cells; stimulate these cells to transcribe steroidogenic acute regulatory protein, and in consequence produce the steroids. [39] [40] 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. [41] 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. [20]

Rat and mouse cells lack OXER1. It has been suggested that the cited 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, 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. [20] 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. [20]

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. [42] It also inhibits morphogenetic protein-2 (BMP-2)-induced bone-like nodule formation in mouse calvarial organ cultures. [43] 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 labor; [44] at 3–150 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; [45] 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. [46] 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. [47] 5(S)-HpETE is also reported to inhibit the Na+/K+-ATPase activity of synaptosome membrane preparations prepared from rat cerebral cortex and may thereby inhibit synapse-dependent communications between neurons. [48]

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. [22] 5(S)-HETE esterified to phosphatidylcholine and glycerol esters by human endothelial cells is reported to be associated with the inhibition of prostaglandin production. [49]

See also

Related Research Articles

<span class="mw-page-title-main">Arachidonic acid</span> Fatty acid used metabolically in many organisms

Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is formed by biosynthesis from linoleic acid in the diet and occurs in animal fats. It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">Leukotriene</span> Class of inflammation mediator molecules

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

<span class="mw-page-title-main">Lipoxygenase</span>

Lipoxygenases (LOX) are a family of (non-heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4-pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

<span class="mw-page-title-main">Mead acid</span> Chemical compound

Mead acid is an omega-9 fatty acid, first characterized by James F. Mead. As with some other omega-9 polyunsaturated fatty acids, animals can make Mead acid de novo. Its elevated presence in the blood is an indication of essential fatty acid deficiency. Mead acid is found in large quantities in cartilage.

<span class="mw-page-title-main">ALOX15</span> Lipoxygenase found in humans

ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function

<span class="mw-page-title-main">ALOX12</span> Protein-coding gene in the species Homo sapiens

ALOX12, also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12S-Lipoxygenase, 12-LOX, and 12S-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ALOX12 gene which is located along with other lipoyxgenases on chromosome 17p13.3. ALOX12 is 75 kilodalton protein composed of 663 amino acids.

<span class="mw-page-title-main">GPR31</span> Protein in humans

G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.

Leukotriene B<sub>4</sub> receptor 2 Protein-coding gene in humans

Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice.

<span class="mw-page-title-main">Oxoeicosanoid receptor 1</span> Protein-coding gene in the species Homo sapiens

Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principal receptor for the 5-Hydroxyicosatetraenoic acid family of carboxy fatty acid metabolites derived from arachidonic acid. The receptor has also been termed hGPCR48, HGPCR48, and R527 but OXER1 is now its preferred designation. OXER1 is a G protein-coupled receptor (GPCR) that is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (GPR81), HCA2, and HCA3 ; OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequence identity with these GPCRs, respectively. It is also related to the recently defined receptor, GPR31, for the hydroxyl-carboxy fatty acid 12-HETE.

<span class="mw-page-title-main">12-Hydroxyeicosatetraenoic acid</span> Chemical compound

12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5Z,8Z,10E,14Z Cis–trans isomerism configuration (Z=cis, E=trans) in its four double bonds. It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase (i.e. ALOX12) enzyme(s). However, the term 12-HETE is ambiguous in that it has been used to indicate not only the initially detected "S" stereoisomer, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE or 12S-HETE), made by platelets, but also the later detected "R" stereoisomer, 12(R)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (also termed 12(R)-HETE or 12R-HETE) made by other tissues through their 12R-lipoxygenase enzyme, ALOX12B. The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. Unlike hormones which are secreted by cells, travel in the circulation to alter the behavior of distant cells, and thereby act as Endocrine signalling agents, these arachidonic acid metabolites act locally as Autocrine signalling and/or Paracrine signaling agents to regulate the behavior of their cells of origin or of nearby cells, respectively. In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances.

<span class="mw-page-title-main">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

<span class="mw-page-title-main">Eoxin</span> Family of proinflammatory eicosanoids

Eoxins are proposed to be a family of proinflammatory eicosanoids. They are produced by human eosinophils, mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues. These cells produce the eoxins by initially metabolizing arachidonic acid, an omega-6 (ω-6) fatty acid, via any enzyme possessing 15-lipoxygenase activity. The product of this initial metabolic step, 15(S)-hydroperoxyeicosatetraenoic acid, is then converted to a series of eoxins by the same enzymes that metabolize the 5-lipoxygenase product of arachidonic acid metabolism, i.e. 5-Hydroperoxy-eicosatetraenoic acid to a series of leukotrienes. That is, the eoxins are 14,15-disubstituted analogs of the 5,6-disubstituted leukotrienes.

<span class="mw-page-title-main">12-Hydroxyheptadecatrienoic acid</span> Chemical compound

12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

<span class="mw-page-title-main">5-Oxo-eicosatetraenoic acid</span> Chemical compound

5-Oxo-eicosatetraenoic acid is a nonclassic eicosanoid metabolite of arachidonic acid and the most potent naturally occurring member of the 5-HETE family of cell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell and/or exits this cell to stimulate nearby cells. 5-Oxo-ETE can stimulate various cell types particularly human leukocytes but possesses its highest potency and power in stimulating the human eosinophil type of leukocyte. It is therefore suggested to be formed during and to be an important contributor to the formation and progression of eosinophil-based allergic reactions; it is also suggested that 5-oxo-ETE contributes to the development of inflammation, cancer cell growth, and other pathological and physiological events.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

References

  1. ↑ Borgeat P, Hamberg M, Samuelsson B (December 1976). "Transformation of arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases". The Journal of Biological Chemistry. 251 (24): 7816–20. doi: 10.1016/S0021-9258(19)57008-9 . PMID   826538.
  2. 1 2 Rossi AG, O'Flaherty JT (December 1991). "Bioactions of 5-hydroxyicosatetraenoate and its interaction with platelet-activating factor". Lipids. 26 (12): 1184–8. doi:10.1007/bf02536528. PMID   1668115. S2CID   3964822.
  3. 1 2 O'Flaherty JT, Taylor JS, Thomas MJ (December 1998). "Receptors for the 5-oxo class of eicosanoids in neutrophils". The Journal of Biological Chemistry. 273 (49): 32535–41. doi: 10.1074/jbc.273.49.32535 . PMID   9829988.
  4. ↑ Powell WS, Rokach J (Mar 2005). "Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE". Progress in Lipid Research. 44 (2–3): 154–83. doi:10.1016/j.plipres.2005.04.002. PMID   15893379.
  5. 1 2 Rådmark O, Werz O, Steinhilber D, Samuelsson B (April 2015). "5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 331–9. doi:10.1016/j.bbalip.2014.08.012. PMID   25152163.
  6. ↑ Osher E, Weisinger G, Limor R, Tordjman K, Stern N (June 2006). "The 5 lipoxygenase system in the vasculature: emerging role in health and disease". Molecular and Cellular Endocrinology. 252 (1–2): 201–6. doi:10.1016/j.mce.2006.03.038. PMID   16647809. S2CID   17299214.
  7. ↑ Moore GY, Pidgeon GP (2017). "Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway". International Journal of Molecular Sciences. 18 (2): 236. doi: 10.3390/ijms18020236 . PMC   5343774 . PMID   28125014.
  8. ↑ Bishayee K, Khuda-Bukhsh AR (September 2013). "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochimica et Biophysica Sinica. 45 (9): 709–19. doi: 10.1093/abbs/gmt064 . PMID   23752617.
  9. ↑ Schneider C, Pozzi A (2011). "Cyclooxygenases and lipoxygenases in cancer". Cancer and Metastasis Reviews. 30 (3–4): 277–94. doi:10.1007/s10555-011-9310-3. PMC   3798028 . PMID   22002716.
  10. ↑ Powell WS, Rokach J (2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Progress in Lipid Research. 52 (4): 651–65. doi:10.1016/j.plipres.2013.09.001. PMC   5710732 . PMID   24056189.
  11. ↑ O'Flaherty JT, Thomas MJ, Lees CJ, McCall CE (1981). "Neutrophil-aggregating activity of monohydroxyeicosatetraenoic acids". The American Journal of Pathology. 104 (1): 55–62. PMC   1903737 . PMID   7258296.
  12. 1 2 3 4 5 6 7 8 Powell WS, Rokach J (April 2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMC   5710736 . PMID   25449650.
  13. ↑ Serhan CN (2005). "Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 73 (3–4): 141–62. doi:10.1016/j.plefa.2005.05.002. PMID   16005201.
  14. ↑ Tejera N, Boeglin WE, Suzuki T, Schneider C (January 2012). "COX-2-dependent and -independent biosynthesis of dihydroxy-arachidonic acids in activated human leukocytes". Journal of Lipid Research. 53 (1): 87–94. doi: 10.1194/jlr.M017822 . PMC   3243484 . PMID   22068350.
  15. ↑ Romano, M; Cianci, E; Simiele, F; Recchiuti, A (2015). "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation". European Journal of Pharmacology. 760: 49–63. doi:10.1016/j.ejphar.2015.03.083. PMID   25895638.
  16. ↑ O'Flaherty JT, Rossi AG (July 1993). "5-hydroxyicosatetraenoate stimulates neutrophils by a stereospecific, G protein-linked mechanism". The Journal of Biological Chemistry. 268 (20): 14708–14. doi: 10.1016/S0021-9258(18)82391-2 . PMID   8392058.
  17. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Powell WS, Rokach J (October 2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Progress in Lipid Research. 52 (4): 651–65. doi:10.1016/j.plipres.2013.09.001. PMC   5710732 . PMID   24056189.
  18. ↑ O'Flaherty JT, Cordes JF, Lee SL, Samuel M, Thomas MJ (December 1994). "Chemical and biological characterization of oxo-eicosatetraenoic acids". Biochimica et Biophysica Acta (BBA) - General Subjects. 1201 (3): 505–15. doi:10.1016/0304-4165(94)90083-3. PMID   7803484.
  19. 1 2 3 4 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 (August 2015). "Biosynthesis and actions of 5-oxoeicosatetraenoic acid (5-oxo-ETE) on feline granulocytes". Biochemical Pharmacology. 96 (3): 247–55. doi:10.1016/j.bcp.2015.05.009. PMC   4830392 . PMID   26032638.
  20. 1 2 3 4 5 Cooke M, Di Cónsoli H, Maloberti P, Cornejo Maciel F (May 2013). "Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells". Molecular and Cellular Endocrinology. 371 (1–2): 71–8. doi:10.1016/j.mce.2012.11.003. hdl: 11336/8381 . PMID   23159987. S2CID   8520991.
  21. 1 2 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 (October 2005). "5-Oxo-ETE analogs and the proliferation of cancer cells". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1736 (3): 228–36. doi:10.1016/j.bbalip.2005.08.009. PMID   16154383.
  22. 1 2 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 (February 2011). "Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection". Blood. 117 (6): 2033–43. doi:10.1182/blood-2010-04-278887. PMC   3374621 . PMID   21177434.
  23. 1 2 Morin C, Sirois M, Echave V, Gomes MM, Rousseau E (June 2007). "Relaxing effects of 5-oxo-ETE on human bronchi involve BK Ca channel activation". Prostaglandins & Other Lipid Mediators. 83 (4): 311–9. doi:10.1016/j.prostaglandins.2007.03.001. PMID   17499751.
  24. ↑ Enyedi B, Kala S, Nikolich-Zugich T, Niethammer P (September 2013). "Tissue damage detection by osmotic surveillance". Nature Cell Biology. 15 (9): 1123–30. doi:10.1038/ncb2818. PMC   3826879 . PMID   23934216.
  25. ↑ Grant GE, Rokach J, Powell WS (September 2009). "5-Oxo-ETE and the OXE receptor". Prostaglandins & Other Lipid Mediators. 89 (3–4): 98–104. doi:10.1016/j.prostaglandins.2009.05.002. PMC   2906239 . PMID   19450703.
  26. ↑ Dworski R, Fitzgerald GA, Oates JA, Sheller JR (April 1994). "Effect of oral prednisone on airway inflammatory mediators in atopic asthma". American Journal of Respiratory and Critical Care Medicine. 149 (4 Pt 1): 953–9. doi:10.1164/ajrccm.149.4.8143061. PMID   8143061.
  27. ↑ O'Flaherty JT, Kuroki M, Nixon AB, Wijkander J, Yee E, Lee SL, Smitherman PK, Wykle RL, Daniel LW (July 1996). "5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes". Journal of Immunology. 157 (1): 336–42. doi: 10.4049/jimmunol.157.1.336 . PMID   8683135. S2CID   35264541.
  28. ↑ Chilton FH, O'Flaherty JT, Walsh CE, Thomas MJ, Wykle RL, DeChatelet LR, Waite BM (May 1982). "Platelet activating factor. Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine". The Journal of Biological Chemistry. 257 (10): 5402–7. doi: 10.1016/S0021-9258(19)83790-0 . PMID   6802816.
  29. ↑ Swendsen CL, Ellis JM, Chilton FH, O'Flaherty JT, Wykle RL (May 1983). "1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine: a novel source of arachidonic acid in neutrophils stimulated by the calcium ionophore A23187". Biochemical and Biophysical Research Communications. 113 (1): 72–9. doi:10.1016/0006-291x(83)90433-3. PMID   6407484.
  30. ↑ Wijkander J, O'Flaherty JT, Nixon AB, Wykle RL (November 1995). "5-Lipoxygenase products modulate the activity of the 85-kDa phospholipase A2 in human neutrophils". The Journal of Biological Chemistry. 270 (44): 26543–9. doi: 10.1074/jbc.270.44.26543 . PMID   7592874.
  31. ↑ Rubin P, Mollison KW (May 2007). "Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids". Prostaglandins & Other Lipid Mediators. 83 (3): 188–97. doi:10.1016/j.prostaglandins.2007.01.005. PMID   17481554.
  32. ↑ Copas JL, Borgeat P, Gardiner PJ (February 1982). "The actions of 5-, 12-, and 15-HETE on tracheobronchial smooth muscle". Prostaglandins, Leukotrienes, and Medicine. 8 (2): 105–14. doi:10.1016/s0262-1746(82)80002-4. PMID   6952280.
  33. ↑ Morin C, Rousseau E (January 2007). "Effects of 5-oxo-ETE and 14,15-EET on reactivity and Ca2+ sensitivity in guinea pig bronchi". Prostaglandins & Other Lipid Mediators. 82 (1–4): 30–41. doi:10.1016/j.prostaglandins.2006.05.012. PMID   17164130.
  34. ↑ Mercier F, Morin C, Cloutier M, Proteau S, Rokach J, Powell WS, Rousseau E (October 2004). "5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca2+ pools and Rho-kinase pathway". American Journal of Physiology. Lung Cellular and Molecular Physiology. 287 (4): L631–40. doi:10.1152/ajplung.00005.2004. PMID   15090369. S2CID   22972003.
  35. ↑ Avis IM, Jett M, Boyle T, Vos MD, Moody T, Treston AM, Martínez A, Mulshine JL (February 1996). "Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling". The Journal of Clinical Investigation. 97 (3): 806–13. doi:10.1172/JCI118480. PMC   507119 . PMID   8609238.
  36. ↑ Ding XZ, Tong WG, Adrian TE (2003). "Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer". Oncology. 65 (4): 285–94. doi:10.1159/000074640. PMID   14707447. S2CID   22159108.
  37. ↑ Wang J, Yuen BH, Leung PC (February 1989). "Stimulation of progesterone and prostaglandin E2 production by lipoxygenase metabolites of arachidonic acid". FEBS Letters. 244 (1): 154–8. doi: 10.1016/0014-5793(89)81182-2 . PMID   2494061. S2CID   42436005.
  38. ↑ Reddy GP, Prasad M, Sailesh S, Kumar YV, Reddanna P (June 1993). "Arachidonic acid metabolites as intratesticular factors controlling androgen production". International Journal of Andrology. 16 (3): 227–33. doi: 10.1111/j.1365-2605.1993.tb01184.x . PMID   8359939.
  39. ↑ Wang XJ, Dyson MT, Jo Y, Eubank DW, Stocco DM (June 2003). "Involvement of 5-lipoxygenase metabolites of arachidonic acid in cyclic AMP-stimulated steroidogenesis and steroidogenic acute regulatory protein gene expression". The Journal of Steroid Biochemistry and Molecular Biology. 85 (2–5): 159–66. doi:10.1016/s0960-0760(03)00189-4. PMID   12943700. S2CID   36071655.
  40. ↑ Wang X, Walsh LP, Reinhart AJ, Stocco DM (June 2000). "The role of arachidonic acid in steroidogenesis and steroidogenic acute regulatory (StAR) gene and protein expression". The Journal of Biological Chemistry. 275 (26): 20204–9. doi: 10.1074/jbc.m003113200 . PMID   10777507.
  41. ↑ Wang XJ, Dyson MT, Mondillo C, Patrignani Z, Pignataro O, Stocco DM (February 2002). "Interaction between arachidonic acid and cAMP signaling pathways enhances steroidogenesis and StAR gene expression in MA-10 Leydig tumor cells". Molecular and Cellular Endocrinology. 188 (1–2): 55–63. doi:10.1016/S0303-7207(01)00748-1. hdl: 11336/36241 . PMID   11911946. S2CID   30710602.
  42. ↑ Gallwitz WE, Mundy GR, Lee CH, Qiao M, Roodman GD, Raftery M, Gaskell SJ, Bonewald LF (May 1993). "5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices". The Journal of Biological Chemistry. 268 (14): 10087–94. doi: 10.1016/S0021-9258(18)82175-5 . PMID   8486677.
  43. ↑ Traianedes K, Dallas MR, Garrett IR, Mundy GR, Bonewald LF (July 1998). "5-Lipoxygenase metabolites inhibit bone formation in vitro". Endocrinology. 139 (7): 3178–84. doi: 10.1210/endo.139.7.6115 . PMID   9645691.
  44. ↑ Pearson T, Zhang J, Arya P, Warren AY, Ortori C, Fakis A, Khan RN, Barrett DA (December 2010). "Measurement of vasoactive metabolites (hydroxyeicosatetraenoic and epoxyeicosatrienoic acids) in uterine tissues of normal and compromised human pregnancy". Journal of Hypertension. 28 (12): 2429–37. doi:10.1097/HJH.0b013e32833e86aa. PMID   20852449. S2CID   27983033.
  45. ↑ Bennett PR, Elder MG, Myatt L (June 1987). "The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility". Prostaglandins. 33 (6): 837–44. doi:10.1016/0090-6980(87)90112-2. PMID   2823315.
  46. ↑ Bennett PR, Chamberlain GV, Patel L, Elder MG, Myatt L (March 1990). "Mechanisms of parturition: the transfer of prostaglandin E2 and 5-hydroxyeicosatetraenoic acid across fetal membranes". American Journal of Obstetrics and Gynecology. 162 (3): 683–7. doi:10.1016/0002-9378(90)90984-F. PMID   2316568.
  47. ↑ Boron WF, Boulpaep EL (2005). Medical physiology : a cellular and molecular approach (Updated ed.). Philadelphia, Pa.: Elsevier Saunders. ISBN   978-1416023289.
  48. ↑ Foley TD (June 1997). "5-HPETE is a potent inhibitor of neuronal Na+, K+-ATPase activity". Biochemical and Biophysical Research Communications. 235 (2): 374–6. doi:10.1006/bbrc.1997.6790. PMID   9199200.
  49. ↑ Richards CF, Johnson AR, Campbell WB (February 1986). "Specific incorporation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid into phosphatidylcholine in human endothelial cells". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 875 (3): 569–81. doi:10.1016/0005-2760(86)90079-2. PMID   3004591.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.