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| Names | |
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| Preferred IUPAC name (6E,8Z,11Z,14Z)-5-Oxoicosa-6,8,11,14-tetraenoic acid | |
Other names
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| Identifiers | |
3D model (JSmol) | |
| ChEBI | |
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| Properties | |
| C20H30O3 | |
| Molar mass | 318.457 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
5-Oxo-eicosatetraenoic acid (i.e. 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid; also termed5-oxo-ETE and5-oxoETE) is anonclassic eicosanoid metabolite ofarachidonic acid and the most potent naturally occurring member of the5-HETE family ofcell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell (seeAutocrine signaling) and/or exits this cell to stimulate nearby cells (seeParacrine signaling). 5-Oxo-ETE can stimulate various cell types particularly humanleukocytes but possesses its highest potency and power in stimulating the humaneosinophil 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;[1][2] it is also suggested that 5-oxo-ETE contributes to the development ofinflammation, cancer cell growth, and other pathological and physiological events.[1][3]
In the most common means for its production, cells make 5-oxo-ETE in a four step pathway that involves their stimulus-induced activation of the following pathway:a) the release of arachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) from its storage sites in membranephospholipids due to the activation ofphospholipase A2 enzymes;b) oxygenation of this arachidonic acid by activatedarachidonate 5-lipoxygenase (ALOX5) to form 5(S)-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5(S)-HpETE);c) reduction of this 5(S)-HpETE by ubiquitous cellular peroxidases to form 5(S)-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5(S)-HETE); and (d) the oxidation of 5(S)-HETE by amicrosome-boundnicotinamide adenine dinucleotide phosphate (NADP+)-dependent dehydrogenase enzyme viz.,5-hydroxyeicosanoid dehydrogenase (5-HEDH), to form 5-oxo-ETE:[1]
5-HEDH has little or no ability to metabolize theRstereoisomer of 5(S)-HETE viz., 5(R)-HETE, to 5-oxo-ETE. Furthermore, it acts in a fully reversible manner, readily converting 5-oxo-ETE back to 5(S)-HETE. Since cells typically maintain very high levels of NADPH compared to their NADP+ levels, they generally have little or no ability to convert 5(S)-HEE to 5-oxo-ETE, and when confronted with 5-oxo-ETE rapidly metabolize it to 5(S)-HETE.[1] However, cells undergoing aging, senescence,apoptosis,oxidative stress, or other conditions that raise their levels ofreactive oxygen species (e.g.superoxide anion,oxygen radicals, andperoxides) either physiologically (e.g. humanphagocytes engulfing bacteria) or pathologically (e.g. oxidatively challengedB-lymphocytes) use up NADP+, have low NADPH/NADP+ ratios, and therefore readily convert 5(S)-HETE to 5-oxo-ETE.[1] Thus, many pathological conditions that involve oxidative stress such as occurs in rapidly growing cancers may be important promoters of 5-oxo-ETE accumulationin vivo.
5-Oxo-ETE can also be made from either 5(S)-HpETE (and possibly 5(R)-HpEPE) by the action ofcytochrome P450 (CYP) enzymes such asCYP1A1,CYP1A2,CYP1B1, andCYP2S1,[4] or from 5(S)-HETE (and probably 5(R)-HETE) by the non-enzymatic attack withheme or various other dehydrating agents.[1] It may also form by the conversion of 5-(S)-HpETE or 5(R)-HpETE to 5-oxo-ETE due to the action of a mousemacrophage 50–60kilodalton cytosolic protein.[5] The contribution of the latter three pathways to the physiological production of 5-oxo-ETE has not been fully evaluated.
An isomer of 5-oxo-ETE, 5-oxo-(7E,9E,11Z,14Z)-eicosatetraenoic acid, forms non-enzymatically as a byproduct of hydrolyses of the 5-lipoxgenase metabolite,leukotriene A4. This byproduct differs from 5-oxo-ETE not only in the position and geometry of its double bounds but also in its activity: it stimulates human neutrophils apparently by acting on one or more LTB4 receptors rather than OXER1.[1][6]
Humanneutrophils,monocytes,eosinophils,B-lymphocytes,dendritic cells,platelets, airwayepithelial cells andsmooth muscle cells, vascularendothelial cells, and skinkeratinocytes have been found and/or suggested to make 5-oxo-ETE from endogenous or exogenous 5-HETE, particularly under conditions of oxidative stress; cell lines derived from human cancers such as those from breast, prostate, lung, colon, and various types of leukemia have likewise been shown to be producers of 5-oxo-ETE.[3]
Cells of one type may release the 5(S)-HETE that they make to nearby cells of a second type which then oxidize the 5(S)-HETE to 5-oxo-ETE. Thistranscellular production typically involves the limited variety of cell types that express active 5-lipoxygenase, lack HEDH activity because of their high levels of NADPH compared to NADP+ levels, and therefore accumulate 5(S)-HETE, not 5-oxo-ETE, upon stimulation. This 5(S)-ETE can leave these cells, enter various cell types that possess 5-HEDH activity along with lower NADPH to NADP+ levels, and thereby be converted to 5-oxo-ETE. Transcellular production of 5-oxo-eicosatetraenoates has been demonstratedin vitro with human neutrophils as the 5(S)-HETE producing cells and humanPC-3 prostate cancer cells,platelets, andmonocyte-deriveddendritic cells as the oxidizing cells.[3][7] It is theorized that this transcellular metabolism occursin vivo and provides a mechanism for controlling 5-oxo-ETE production by allowing it to occur or be augmented at sites were 5-lipoxygenase-containing cells congregate with cell types possessing 5-HEDH and favorable NADPH/NADP+ ratios; such sites, it is theorized, might include those involving allergy, inflammation, oxidative stress, and rapidly growing cancers.[1][3]
As indicated in the previous section, 5-oxo-ETE is readily converted to 5(S)-HETE by 5-HEDH in cells containing very low NADPH/NADP+ ratios. Humanneutrophils, an important model cell for investigating 5-oxo-ETE production, take up 5-oxo-ETE and reduce it to 5(S)-HETE; they also form appreciable amounts of 5(S)-20-dihydroxy-ETE and small amounts of 5-oxo,20-hydroxy-ETE probably by the action of the ω-hydroxylasecytochrome P450 enzyme, CYP453A on 5(S)-HETE and 5-oxo-ETE, respectively.[3][8] The cells also incorporate the 5(S)-HETE product of 5-oxo-ETE but little or no 5-oxo-ETE itself as anester into variousphospholipid andglycerolipid pools; however, isolated neutrophilplasma membranes, which lack appreciable 5-HEDH activity, do esterify 5-oxo-ETE into these lipid pools.[1][8]
Several other pathways can metabolize 5-oxo-ETE. First, humaneosinophils usearachidonate 15-lipoxygenase-1 (or possiblyarachidonate 15-lipoxygenase-2 to metabolize 5-oxo-ETE to 5-oxo-15-(S)-hydroperoxy-ETE which is rapidly reduced to 5-oxo-15(S)-hydroxy-ETE; 5-oxo-15(S)-hydroxyl-ETE is about one-third as potent as 5-oxo-ETE in stimulating cells.[1][3] Second, human platelets use12-lipoxygenase to metabolize 5-oxo-ETE to 5-oxo-12(S)-hydroperoxy-eicosatetraenoate, which is rapidly converted to 5-oxo-12(S)-hydroxy-eicosatetraenoate (5-oxo-12(S)-hydroxy-ETE); 5-oxo-12(S)-hydroxyl-ETE is a weak antagonist of 5-oxo-ETE.[3] Third, mousemacrophages usea) acytochrome P450 enzyme to metabolize 5-oxo-ETE to 5-oxo-18-hydroxy-ETE (5-oxo-18-HETE) which is either attacked by a 5-keto-reductase (possibly 5-HEDH) to form 5,18-dihydroxy-eicosatetraenoic acid (5,18-diHETE) or by a Δ6-reductase to form 5-oxo-18-hydroxy-eicosatrienoic acid (5-oxo-18-HETrE) which is then reduced by a 5-keto-reductase (possibly 5-HEDH) to 5,18-dihydroxy-eicosatrienoic acid (5,18-diHETrE);b) a cytochrome P450 enzyme converts 5-oxo-ETE to 5-oxo-19-hydroxy-eicosatetraenoic acid (5-oxo-19-HETE) which is then either reduced by a keto reductase (possibly 5-HEDH) to 5,19-dihydroxy-eicosatetraenoic acid (5,19-diHETE) or by a Δ6 reductase to 5-oxo-19-hydroxy-eicosatrienoic acid (5-oxo-19-HETrE);[9] orc) leukotriene C4 synthase to metabolize 5-oxo-ETE to 5-oxo-7-glutathionyl-8,11,14-eicosatrienoic acid (FOG7). FOG7 simulates cells by a different mechanism than 5-oxo-ETE; the biological activity of the other mouse-derived metabolites has not been reported.[10][11]
Studies in human neutrophils first detected aplasma membrane-localized site which reversibly bound 5-oxo-ETE and had the attributes of aGi alpha subunit-linkedG protein-coupled receptor based on the ability of 5-oxo-ETE to activate this class of membrane G proteins by apertussis toxin-sensitive mechanism.[3][8] Subsequently, this receptor was cloned by several groups who termed it theoxoeicosanoid receptor 1 (OXER1), OXE, OXE-R, hGPCR48, HGPCR48, or R527 (its gene is termedOXE1 orOXER1), and found it coupled with and activated theG protein complex composed of theGi alpha subunit (Gαi) andG beta-gamma complex (Gβγ).[1][3][12] When bound by 5-oxo-ETE, the OXER1 triggers this G protein complex to dissociate into its Gαi and Gβγ components; dissociated Gβγ is responsible for activating many of the signal pathways that lead to the cellular functional responses elicited by 5-oxo-ETE.[13] These signaling pathways include those evoking rises incalcium ion levels as well as others that activateMAPK/ERK,p38 mitogen-activated protein kinases, cytosolicphospholipase A2,PI3K/Akt,protein kinase C beta (PKCβ), and/or (PKCε).[1][3][12][14] Most actions of the 5-oxo-ETE appear mediated by OXER1; however, some of its cell-stimulating actions appear to be OXER1-independent, as indicated in the following section. Other compounds can also stimulate cells through OXER1. Many of these compounds differ slightly from 5-oxo-ETE in structure by the replacement of one atom by an atom of a different element, by the loss of one or more atoms, and/or by the presence of afunctional group not found in 5-oxo-ETE. These compounds are termed 5-oxo-ETE analogs or members of the 5-oxo-ETE family of agonists. 5-HETE and 5-hydroxy-15(S)-hydroxyeicosatetraenoic acid are examples of such analogs. 5-Oxo-ETE and many of its analogs are produced by human cells, other mammalian cells such as those from cats and opossums, and the cells of several species of fish.[2][3] Based on the presence of itsmRNA, the OXER1 receptor is assumed to be highly expressed in human bloodeosinophils, neutrophils, spleen, lung, liver and kidney and at lower levels in human basophils, monocytes, lungmacrophages, and various human cancer cell lines, and acell line derived from the humanadrenal cortex; however, the cells of mice and rats appear to lack a clear OXER1.[1]
Mouse MA-10 cells respond to 5-oxo-ETE but lack OXER1. It has been suggested that these cells' responses to 5-oxo-ETE are mediated by an ortholog to OXER1, mouseniacin receptor 1, Niacr1, which is a G protein-coupled receptor forniacin, or, alternatively, 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.[3][15]
5-Oxo-ETE and 5-oxo-15(S)-hydroxy-ETE but not 5-hydroxy members of the 5-HETE family such as 5-(S)-HETE activateperoxisome proliferator-activated receptor gamma (PPARγ). This activation does not proceed through OXER1; rather, it involves the direct binding of the oxo analog to PPARγ with 5-oxo-15-(S)-hydroxy-ETE being more potent than 5-oxo-ETE in binding and activating PPARγ.[16] The Activation of OXER1 receptor and PPARγ by the oxo analogs can have opposing effects on cell function. For example, 5-oxo-ETE-bound OXER1 stimulates whereas 5-oxo-ETE-bound PPARγ inhibits the proliferation of various types of human cancer cell lines; this results in 5-oxo-ETE and 5-oxo-15-(S)-HETE having considerably less potency than anticipated in stimulating these cancer cells to proliferate relative to the potency of 5-(S)-HETE, a relationship not closely following the potencies of these three compounds in activating OXER1.[3][16]
5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.[3][17]
5-Oxo-ETE is a potentin vitro stimulator and/or enhancer ofchemotaxis (i.e. directional migration) and, depending on the cell type, various other responses such asdegranulation (i.e. release of granule-bound enzymes), oxidative metabolism (i.e. generation ofreactive oxygen species), and production of mediators such as various arachidonic acid metabolites andplatelet-activating factor in human eosinophils,basophils, neutrophils, andmonocytes.[3][18] Furthermore, the injection of 5-oxo-ETE into the skin of humans causes the local accumulation of circulating blood cells, particularly eosinophils but also to lesser extents neutrophils andmonocyte-derivedmacrophages.[19] The activity of 5-oxo-ETE on the two cell types known to be involved in allergy-based inflammation, eosinophils and basophils, suggests that it may be involved in promoting allergic reactions possibly by attracting throughchemotaxis these cells to nascent sites of allergy and/or through stimulating these cells to release granule-bound enzymes, reactive oxygen species, or other promoters of allergic reactions.[3][12] 5-Oxo-ETE's activity on human cells involved in non-allergic inflammatory diseases viz., neutrophils and monocytes, as well as its ability to attract these cell types to the skin of humans suggest that 5-oxo-ETE may also be involved in the broad category of non-allergic inflammatory diseases including those involving host defense against pathogens.[12]
5-Oxo-ETE contracts smooth muscle and organ-cultured bronchi isolated from guinea pigs but relaxes bronchi isolated from human lung; the relaxation of human bronchi caused by 5-oxo-ETE may not involve its OXER1.[3][20] These results suggest that 5-oxo-ETE is not directly involved in thebronchoconstriction) that occurs in eosinophil-based allergicasthma reactions in humans.
5-Oxo-ETE (or other 5-HETE family member) stimulates the growth and/or survival of human cell lines derived from cancers of the prostate, breast, lung, ovary, colon and pancreas[1][3][16][21] These preclinical studies suggest that 5-oxo-ETE (or other 5-HETE family member) may contribute to the cited cancers progression in humans.
5-oxo-ETE stimulates humanH295R adrenocortical cells to increase transcription of steroidogenic acute regulatory protein messenger RNA and producealdosterone andprogesterone by an apparent OXER1-dependent pathway.[15]
5-Oxo-ETE induces an isotonic volume reduction in guinea pig intestinal crypt epithelial cells.[22]
5-Oxo-ETE and another potential mediator of human allergic reactions,platelet-activating factor, act insynergy to stimulate human eosinophils and neutrophils: the combined agents elicit responses that are greater than the simple sum of their individual actions and do so at relatively low.[23][24] 5-Oxo-ETE also greatly increases the potencies ofcomplement component 5a,LTB4, andFMLP in stimulating human eosinophils to degranulate and its degranulating activity is greatly increase by pretreating human eosinophils withgranulocyte-macrophage colony stimulating factor or human neutrophils with either the lattercytokine or withgranulocyte colony-stimulating factor,tumor necrosis factor α, or variousnucleotides includingATP.[23][24][25][26] Pretreament of eosinophils withinterleukin 5 (a key mediator in eosinophil activation) also increases theirin vitro chemotactic response to 5-oxo-ETE.[27] 5-Oxo-ETE also acts in synergy with twochemokines,CCL2 andCCL8, in stimulating monocyte chemotaxis.[18] The interactions of 5-oxo-ETE with these mediators of allergy (e.g. platelet-activating factor, interleukin 5) in eosinophils further suggests that it plays a role in allergic diseases while its interactions with mediators of inflammatory reactions (e.g. tumor necrosis factor α, the colony stimulating factors, and the two CCL chemokines) in neutrophils and monocytes further suggest that it plays a role in inflammatory responses and host defense mechanisms.
Essentially all of the studies on 5-oxo-ETE's activities and target cells, similar to those on other members of the 5(S)-HETE family of agonists, are best classified aspre-clinical development studies: they have not yet been determined to be important in human pathophysiology.Translation studies are needed to learn if the preclinical studies implicating 5-Oxo-ETE and other 5(S)-HETE family members in allergic diseases, inflammatory diseases, cancer, steroid production, bone remodeling, parturition, and other pathophysiological events, as outlined here and on the5-HETE page, are relevant to humans and therefore of clinical significance.
The clinical significance of 5-oxo-ETE has been most frequently studied as a possible mediator of eosinophil-based allergic reactions. When administered as anintradermal injection, it causes the infiltration of eosinophils at the injection site in monkeys. In humans, it induces the infiltration of eosinophils that is accompanied by significant levels of neutrophil and macrophage infiltrations. These 5-oxo-ETE injections caused a significantly larger eosinophil infiltrate in asthmatic compared to healthy humans. Studies in rhesus monkeys that were sensitized to an allergen, showed that the intradermal injection of the original allergen caused a localized accumulation of eosinophils; this infiltration was blocked by ~50% in animals pretreated with an orally taken OXER1 receptor antagonist. This same receptor antagonist likewise blocked the infiltration of eosinophils into the lung in rhesus monkeys that were sensitized to and then challenged with the original allergen. Increased levels of 5-oxo-ETE have been detected in the exhaled breath condensate of humans who developed an asthma-likebronchoconstriction response to the inhalation ofhouse dust mite allergen: the levels of these increases were higher in individuals who developed a more severelate asthmatic response. Similarly, increased levels of 5-oxo-ETE have been detected in thebronchoalveolar lavage fluid following the inhalation of house dust mite allergen to house dust mite-sensitized mice. Finally, the epithelial cells obtained from thenasal polyps of humans produce 5-oxo-ETE and, when applied to cultures of nasal polyp tissue, 5-oxo-ETE stimulates the production ofeosinophil cationic protein, a protein associated with eosinophil-based inflammation and asthma. These results indicate that: 1) 5-oxo-ETE causes skin eosinophil-based allergic-like reactions; 2) its actions, at least in monkeys, involve stimulating the OXER1; 3) 5-oxo-ETE (or a similarly acting 5-oxo-ETE analog) may contribute to human skin (e.g.atopic dermatitis), lung (e.g. asthma), and nasal (e.g.allergic rhinitis) allergic reactions; and 4) OXER1 antagonists may be useful in treating these skin, lung, and, possibly, nasal reactions in humans.[28]