5-oxo-eicosatetraenoic acid

5-oxo-eicosatetraenoic acid
Names
IUPAC name
5-oxo-6E,8Z,11Z,14Z-eicosatetraenoate
Other names
5-oxo-ETE, 5-oxoETE, 5-KETE
Identifiers
106154-18-1
ChEBI CHEBI:52449
Jmol interactive 3D Image
PubChem 5283159
Properties
C20H30O3
Molar mass 318.45
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

5-Oxo-eicosatetraenoic acid (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoate or 5-oxo-ETE; some early studies termed it 5-KETE (K for its 5-Ketone, i.e. 5-oxo, residue) is the most potent naturally occurring member of the 5-HETE family of arachidonic acid metabolites; these metabolites stimulate a variety of cell types including particularly the human eosinophil by binding to the OXER1 receptor.[1] Preclinical studies suggest that 5-oxo-ETE may be a mediator of human allergy and/or certain inflammatory and non-inflammatory pathophysiological responses.[2][3][4]

5-Oxo-ETE production

Cells make 5-oxo-ETE by a) oxygenating arachidonic acid with arachidonate 5-lipoxygenase (ALOX5) to form 5(S)-hydroperoxy-eicosatetraenoic acid (5(S)-HpETE); b) reducing 5(S)-HpETE with cellular peroxidases to form 5(S)-hydroxy-eicosatetraeonic acid (5(S)-HETE), and (c) oxidizing 5(S)-HETE with microsome-bound nicotinamide adenine dinucleotide phosphate (NADP+)-dependent dehydrogenase (5-Hydroxyeicosanoid dehydrogenase or 5-HEDH) to form 5-oxo-ETE (see 5-HETE).[5] (5-HEDH has little or no such effect on the R stereoisomer of 5(S)-HETE viz., 5(R)-HETE.) 5-Oxo-ETE can also be made form either 5(S)-HpETE (and possibly 5(R)-HpEPE) by the action of cytochrome P450 (CYP) enzymes such as CYP1A1, CYP1A2, CYP1B1, and CYP2S1.;[6] from 5(S)-HETE (and probably 5(R)-HETE) by the non-enzymatic attack with heme or various other dehydrating agents;[7] and from the 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.[8] The contribution of the latter three pathways to the physiological production of 5-oxo-ETE has not been fully studied; most attention has focused on the 5-HEDH pathway.

5-HEDH acts reversibly with the direction of its 5-(S)-HETE and 5-oxo-ETE interconversions determined by ambient NADPH/NADP+ ratios[9][10] Cells containing high levels of NADPH compared to NADP+ make little or no 5-oxo-ETE from endogenous 5-HETE and rapidly convert exogenous 5-oxo-ETE to 5-(S)-HETE whereas cells containing low levels of NADPH compared to NADP+ convert sizable portions of 5-(S)-HETE to 5-oxo-ETE.[11] Since most cells normally maintain high NADPH/NADP+ ratios, they make little or no 5-oxo-ETE from 5(S)-HETE and rapidly convert exogenous 5-oxo-ETE to 5-(S)-HETE.[12][13] However, cells undergoing aging, senescence, apoptosis, oxidative stress, or other conditions that raise their levels of reactive oxygen species (e.g. superoxide anion, oxygen radicals, and peroxides) either physiologically (e.g. human phagocytes engulfing bacteria) or pathologically (e.g. oxidatively challenged B-lymphocytes) use up NADP+, have low NADPH/NADP+ ratios, and therefore readily convert 5(S)-HETE to 5-oxo-ETE.[14][15][16][17][18][19] Thus, many pathological conditions, including those involving oxidative stress such as occurs in rapidly growing cancers, may be important promoters of 5-oxo-ETE accumulation in vivo.

Human neutrophils, monocytes, eosinophils, B-lymphocytes, dendritic cell, platelets, airway epithelial cells and smooth muscle cells, vascular endothelial cells, and skin keratinocytes 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.[20] The production of 5-oxo-ETE by these cells often involves transcellular metabolism wherein cells of one type make 5(S)-HETE and release it to nearby cells of a second type which then oxidize the 5(S)-HETE to 5-oxo-ETE. This sharing of responsibilities, at least in in vitro studies, typically involves the limited number of cell types that express active 5-lipoxygenase and therefore act as donors that deliver 5(S)-HETE to the far larger number of cell types that contain 5-HEDH and/or possess lower NADPH/NADP+ ratios than the donor cells. The transcellular production of 5-oxo-eicosatetraenoates has been demonstrated in vitro with human neutrophils as the 5(S)-HETE producers and human PC-3 prostate cancer cells, platelets, and monocyte-derived dendritic cells as the oxidizing cells.[21][22] It is theorized that this transcellular metabolism occurs in vivo and provides a mechanism for controlling 5-oxo-ETE production by allowing it to occur of be greatly augmented at sites were 5-lipoxygenase-containg cells congregate with cell types possessing 5-HEDH and favorable NADPH/NADP+ ratios; such sites might include those involving allergy, inflammation, oxidative stress, and rapidly growing cancers.

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-lipooxgenase 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.[23]

5-Oxo-ETE metabolism

As indicated in the previous section, 5-oxo-ETE is readily converted to 5(S)-HETE by 5-HEDH in cells containing high NADPH/NADP+ ratios. Human neutrophils, 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 far smaller amounts of 5-oxo,20-hydroxy-ETE probably by the action of the ω-hydroxylase cytochrome P450 enzyme, CYP453A.[13][24] The cells also incorporate the 5(S)-HETE product of 5-oxo-ETE but little or no 5-oxo-ETE itself as an ester into their various phospholipid and glycerolipid pools; however, isolated neutrophil plasma membranes, which lack appreciable 5-HEDH activity, do esterify 5-oxo-ETE into these lipid pools.[13]

In addition to the above metabolic pathways: a) human eosinophils may use Arachidonate 15-lipoxygenase-1 (or possibly Arachidonate 15-lipoxygenase-2 to oxygenate 5-oxo-ETE to make 5-oxo-15-(S)-hydroperoxy-ETE which is then converted to 5-oxo-15(S)-hydroxy-ETE; b) human platelets use 12-lipoxygenase to oxygenate 5-oxo-ETE to make 5-oxo-12(S)-hydroxy-eicosatetraenoat which is then converted to 5-oxo-12(S)-hydroxy-eicosatetraenoate (5-oxo-12-hydroxy-ETE);[25] c) a cytochrome P450 enzyme in mouse macrophages converts 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-eicosatetrienoic acid (5,18-diHETrE); d) a cytochrome P450 enzyme in mouse macrophages 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);[26] and e) leukotriene C4 synthase in mice metabolizes 5-oxo-ETE to 5-oxo-7-glutathionyl-8,11,14-eicosatrienoic acid (FOG7).[27][28]

5-Oxo-ETE's mechanism of action

The OXER1 receptor

Studies in human neutrophils first detected a plasma membrane-localized site which reversibly bound 5-oxo-ETE;[13] this binding site had the attributes of a Gi alpha subunit-linked G protein-coupled receptor based on the ability of 5-oxo-ETE to activate this class of membrane G proteins by a pertussis toxin-sensitive mechanism.[29] The binding and G protein-activating potencies of various members of the 5-HETE family of agonists including 5-oxo-ETE and 5-oxo-15-hydroxy-ETE paralleled their ability to stimulate neutrophil functional responses (see 5-HETE). Subsequently, this receptor was cloned by several groups who termed it oxoeicosanoid receptor 1 (OXER1), OXE, OXE-R, hGPCR48, HGPCR48, and R527 (its gene is termed OXE1 or OXER1), and, as predicted by the cited binding studies, found it coupled with and activated the G protein complex composed of the Gi alpha subunit (Gαi) and G beta-gamma complex (Gβγ).[13][30][31][32][25][33][34]

When bound by 5-oxo-ETE or other 5-HETE family member OXER1 triggered this G protein complex to dissociate into its Gαi and Gβγ components.[13][35] with Gβγ being responsible for activating many of the signal pathways that lead to the cellular functional responses elicited by the 5-HETE family of agonists.[36] The cell-activation pathways stimulated by OXER1 include those evoking rises in cytosolic calcium ion levels,[37][38][39] as well as those activating MAPK/ERK, p38 mitogen-activated protein kinases, cytosolic Phospholipase A2, PI3K/Akt, protein kinase C beta (PKCβ), and protein kinase C epsilon (PKCε).[32][40][41][42][43][44] 5-Oxo-ETE also stimulates human neutrophils to activate cytosolic phospholipase A2 (cPLA2) and increase these cells' activation of cPLA2 as well as cPLA2-induced release of arachidonic acid elicited by other stimuli.[45]

OXER1 mRNA is highly expressed in human blood eosinophils, neutrophils, spleen, lung, liver and kidney; this mRNA is expressed at lower levels in human basophils, monocytes, lung macrophages, various cancer cell lines, and an adrenocortical cell line.[46] Orthologs of OXER1 are found in various mammalian species including cats and opossums as well as several species of fish; however, mice and rats lack a clear ortholog of OXER1.[47][48]

Most actions of the 5-HETE family of agonists appear mediated by OXER1. Some of their actions, however, appear to be OXER1-independent, as indicated below.

Other GPCR receptors

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, mouse niacin receptor 1, Niacr1, which is a G protein-coupled receptor for niacin, 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.[49]

PPARγ

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 activate peroxisome 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.[50] 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.[50]

Other mechanisms

5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.[22][51]

5-Oxo-ETE's target cells

Inflammatory cells

5-Oxo-ETE is a potent in vitro stimulator and/or enhancer of chemotaxis (i.e. directional migration) and, depending on the cell type, various other responses such as degranulation (i.e. release of granule-bound enzymes), oxidative metabolism (i.e. generation of reactive oxygen species), and production of mediators such as various arachidonic acid metabolites and platelet-activating factor in human eosinophils, basophils, neutrophils, and monocytes.[22][52][53][54][55][56] Indeed, the injection of 5-oxo-ETE into the skin of humans causes the local accumulation of eosinophils and to lesser extents neutrophils and monocyte-derived macrophages.[57] 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 through chemotaxis 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. 5-Oxo-ETE's activity on human cells involved in non-allergic inflammatory diseases viz., neutrophils and monocytes, as well as its ability to attack 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.

Lung airway smooth muscle cells

5-Oxo-ETE contracts smooth muscle and organ-cultured bronchi isolated from guinea pigs,[58][59] but relaxes bronchi isolated from human lung.[60] The relaxation of human bronchi caused by 5-oxo-ETE may not involve its OXER1.[61][62] In any event, these results suggest that 5-oxo-ETE is not directly involved in the bronchoconstriction) that occurs in eosinophil-based allergic asthma reactions in humans.

Cancer cells

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;[40][63][64] breast;[50][65] lung;[66][67] Ovary;[50][68] colon;,[69] and pancreas.[41][70] These preclinical studies suggest that 5-oxo-ETE (or other 5-HETE family member) may contribute to the cited cancers progression in humans.

Steroidogenic cells

5-oxo-ETE stimulates human H295R adrenocortical cells to increase transcription of steroidogenic acute regulatory protein messenger RNA and produce aldosterone and progesterone by an apparent OXER1-dependent pathway.[71]

Other cell types

5-Oxo-ETE induces an isotonic volume reduction in guinea pig intestinal crypt epithelial cells.[72]

5-Oxo-ETE's interaction with other stimuli

5-Oxo-ETE and another potential mediator of human allergic reactions, platelet-activating factor, act in Synergy in stimulating 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.[73][74] 5-Oxo-ETE also greatly increases the potencies of Complement component 5a, LTB4, and FMLP in stimulating human eosinophils to degranulate and its degranulating activity is greatly increase by pretreating human eosinophils with granulocyte-macrophage colony stimulating factor or human neutrophils with either the latter cytokine or with granulocyte colony-stimulating factor, Tumor necrosis factor α, or various nucleotides including ATP.[75][76][77][78] Pretreament of eosinophils with interleukin 5 (a key mediator in eosinophil activation) also increases their in vitro chemotactic response to 5-oxo-ETE.[79] 5-Oxo-ETE also acts in synergy with two chemokines, CCL2 and CCL8, in stimulating monocyte chemotaxis.[80] 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.

Clinical significance

5-Oxo-ETE may be involved in human allergic diseases, inflammatory diseases, cancers, and steroid production, as indicated above, as well as in human bone remodeling, parturition, and other clinically significant events. Some of the studies suggesting these associations examined 5(S)-HETE but were conducted before the discovery of 5-oxo-ETE and/or focused on other members of the 5-HETE family of agonists besides 5-oxo-ETE. See the 5-HETE page for a fuller description of the clinical significance of this family of agonists.

See also

References

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