5-Oxo-eicosatetraenoic acid

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5-Oxo-eicosatetraenoic acid
Names
Preferred IUPAC name
(6E,8Z,11Z,14Z)-5-Oxoicosa-6,8,11,14-tetraenoic acid
Other names
  • 5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoate
  • 5-oxo-ETE
  • 5-oxoETE
  • 5-KETE
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
KEGG
  • InChI=1S/C20H30O3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-16-19(21)17-15-18-20(22)23/h6-7,9-10,12-14,16H,2-5,8,11,15,17-18H2,1H3,(H,22,23)/b7-6-,10-9-,13-12-,16-14+
    Key: MEASLHGILYBXFO-XTDASVJISA-N
  • CCCCC\C=C/C\C=C/C\C=C/C=C/C(=O)CCCC(O)=O
Properties
C20H30O3
Molar mass 318.457 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

5-Oxo-eicosatetraenoic acid (i.e. 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid; also termed 5-oxo-ETE and 5-oxoETE) is a

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;[1][2] it is also suggested that 5-oxo-ETE contributes to the development of inflammation, cancer cell growth, and other pathological and physiological events.[1][3]

Biochemistry and production

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 membrane

5-hydroxyeicosanoid dehydrogenase (5-HEDH), to form 5-oxo-ETE:[1]

a) Phospholipid-bound arachidonic acid → free arachidonic acid
b) Free arachidonic acid + O2 → 5(S)-HpETE
c) 5(S)-HpETE → 5(S)-HETE
d) 5(S)-HETE + NADP+ 5-oxo-ETE + NADPH

5-HEDH has little or no ability to metabolize the R

B-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 accumulation in vivo.

5-Oxo-ETE can also be made form either 5(S)-HpETE (and possibly 5(R)-HpEPE) by the action of

kilodalton 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]

Tissue sources

Cellular production

Human

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.[3]

Transcellular production

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. This transcellular 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 demonstrated in vitro with human neutrophils as the 5(S)-HETE producing cells and human

PC-3 prostate cancer cells, platelets, and monocyte-derived dendritic cells as the oxidizing cells.[3][7] 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 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]

Metabolism

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. Human

plasma 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, human

12-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, mouse macrophages use a) a cytochrome 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] or c) 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]

Mechanism of action

The OXER1 receptor

Studies in human neutrophils first detected a

cell line derived from the human adrenal cortex; however, the cells of mice and rats appear to lack a clear OXER1.[1]

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

GPR109B), which are G protein-coupled receptors for fatty acids.[3][15]

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.[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]

Other mechanisms

5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.[3][17]

Target cells

Inflammatory cells

5-Oxo-ETE is a potent in vitro stimulator and/or enhancer of

macrophages.[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 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.[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]

Lung airway smooth muscle cells

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 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, 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.

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.[15]

Other cell types

5-Oxo-ETE induces an isotonic volume reduction in guinea pig intestinal crypt epithelial cells.[22]

Interaction with other stimuli

5-Oxo-ETE and another potential mediator of human allergic reactions,

chemokines, CCL2 and CCL8, 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.

Clinical significance

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 as

5-HETE
page, are relevant to humans and therefore of clinical significance.

Potential involvement in allergy

The clinical significance of 5-oxo-ETE has been most frequently studied as a possible mediator of eosinophil-based allergic reactions. When administered as an

nasal polyps of humans produce 5-oxo-ETE and, when applied to cultures of nasal polyp tissue, 5-oxo-ETE stimulates the production of eosinophil 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]

See also

References

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