Epoxydocosapentaenoic acid

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Structure of 19,20-epoxydocosapentaenoic acid, an example of an epoxydocosapentaenoic acid. Both the 19(R),20(S)- and 19(S),20(R)-EDP are produced by epoxygenases. 19,20-EDP.png
Structure of 19,20-epoxydocosapentaenoic acid, an example of an epoxydocosapentaenoic acid. Both the 19(R),20(S)- and 19(S),20(R)-EDP are produced by epoxygenases.

Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides (see Epoxygenase). These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase (sEH; also termed epoxide hydrolase 2). Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs (and EEQs) distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil. [1]

Contents

Structure

EDPs are epoxide eicosapentaenoic acid metabolites of DHA. DHA has 6 cis (see Cis–trans isomerism) double bonds each one of which is located between carbons 4-5, 7-8, 10-11, 13-14, 16-17, or 19-20. Cytochrome P450 epoxygenases attack any one of these double bounds to form a respective docosapentaenoic acid (DPA) epoxide regioisomer (see Structural isomer § Position isomerism (regioisomerism)). A given epoxygenase may therefore convert DHA to 4,5-EDP (i.e. 4,5-epoxy-7Z,10Z,13Z,16Z,19Z-DPA), 7,8-EDP (i.e. 7,8-epoxy-4Z,10Z,13Z,16Z,19Z-DPA), 10,11-EDP (i.e. 10,11-epoxy-4Z,7Z,13Z,16Z,19Z-DPA), 13,14-EDP (i.e. 13,14-epoxy-4Z,7Z,10Z,16Z,19Z-DPA), 16,17-EDP (i.e. 16,17-epoxy-4Z,7Z,10Z,13Z,19Z-DPA, or 19,20-EDP (i.e. 19,20-epoxy-4Z, 7Z,10Z,13Z,16Z-DPA. The epoxygenase enzymes generally form both R/S enantiomers at each former double bound position; for example, cytochrome P450 epoxidases attack DHA at the 16,17-double bond position to form two epoxide enantiomers, 16R,17S-EDP and 16S,17S-EDP. [2] The 4,5-EDP metabolite is unstable and generally not detected among the EDP formed by cells. [3]

Production

Enzymes of the cytochrome P450 (CYP) superfamily that are classified as epoxygenases based on their ability to metabolize PUFA, particularly arachidonic acid, to epoxides include: CYP1A, CYP2B, CYP2C, CYP2E, CYP2J, and within the CYP3A subfamily, CYP3A4. In humans, CYP2C8, CYP2C9, CYP2C19, CYP2J2, and possibly CYP2S1 isoforms appear to be the principal epoxygenases responsible for metabolizing arachidonic acid to EETs (see Epoxyeicosatrienoic acid § Production). In general, these same CYP epoxygenases also metabolize DHA to EDP (as well as EPA to EEQ; CYP2S1 has not yet been tested for DHA-metabolizing ability), doing so at rates that are often greater than their rates in metabolizing arachidonic acid to EETs; that is, DHA (and EPA) appear to be preferred over arachidonic acid as substrates for many of the CYP epoxygenases. [4] CYP1A1, CYP1A2, CYP2C18, CYP2E1, CYP4A11, CYP4F8, and CYP4F12 also metabolize DHA to EDPs. [5] CYP2C8, CYP2C18, CYP2E1, CYP2J2, VYP4A11, CYP4F8, and CYP4F12 preferentially attack the terminal omega-3 double bond that distinguishes DHA from omega-6 fatty acids and therefore metabolize DHA principally to 19,20-EDP isomers while CYP2C19 metabolizes DHA to 7,8-EDP, 10,11-EDP, and 19,20-EDP isomers [5] [6] CYP2J2 metabolizes DHA to EPAs, principally 19,20-EPA, at twice the rate that it metabolizes arachidonic acid to EETs. [7] In addition to the cited CYP's, CYP4A11, CYP4F8, CYP4F12, CYP1A1, CYP1A2, and CYP2E1, which are classified as CYP monooxygenase rather than CYP epoxygeanses because they metabolize arachidonic acid to monohydroxy eicosatetraenoic acids (see 20-Hydroxyeicosatetraenoic acid), i.e. 19-hydroxyeicosatetraenoic acid and/or 20-hydroxyeicosatetranoic acid, take on epoxygease activity in converting DHA primarily to 19,20-EDP isomers (see Epoxyeicosatrienoic acid). [5] The CYP450 epoxygenases capable of metabolizing DHA to EDPs are widely distributed in organs and tissues such as the liver, kidney, heart, lung, pancreas, intestine, blood vessels, blood leukocytes, and brain. [8] [9] These tissues are known to metabolize arachidonic acid to EETs; it has been shown or is presumed that they also metabolize DHA to EPD's. [10] [11] </ref> [12]

The EDPs are commonly made by the stimulation of specific cell types by the same mechanisms which produce EETs (see Epoxyeicosatrienoic acid). That is, cell stimulation causes DHA to be released from the sn-2 position of their membrane-bound cellular phospholipid pools through the action of a phospholipase A2-type enzyme and the subsequent attack of the released DHA by CYP450 epoxidases. It is notable that the consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans. Indeed, this rise in EDP (and EEQ) levels in humans is by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids and, it is suggested, may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids. [1] [13]

EDP metabolism

Similar to EETs (see Epoxyeicosatrienoic acid), EDPs are rapidly metabolized in cells by a cytosolic soluble epoxide hydrolase (sEH, also termed epoxide hydrolase 2 [EC 3.2.2.10.]) to form their corresponding vicinal diol dihydroxyeicosapentaenoic acids. Thus, sEH converts 19,20-EDP to 19,10-dihdroxydocosapentaenoic acid (DPA), 16,17-EDP to 16,17-dihydroxy-DPA, 13,14-EDP to 13,14-dihydroxy-DPA, 10,11-EDP to 10,11-dihydroxy-DPA, and 7,8-EDP to 7,8-dihydroxy-EDP; 4,5-EDP is unstable and therefore generally not detected in cells. [14] The dihydroxy-EDP products, like their epoxy precursors, are enantiomer mixtures; for instance, sEH converts 16,17-EDP to a mixture of 16(S),17(R)-dihydroxy-DPA and 16(R),17(S)-dihydroxy-DPA. [2] These dihydroxy-DPAs typically are far less active than their epoxide precursors. The sEH pathway acts rapidly and is by far the predominant pathway of EDP inactivation; its operation causes EDPs to function as short-lived mediators whose actions are limited to their parent and nearby cells, i.e. they are autocrine and paracrine signaling agents, respectively. [14] [15] [16]

In addition to the sEH pathway, EDPs, similar to the EETs, may be acylated into phospholipids in an acylation-like reaction; this pathway may serve to limit the action of EETs or store them for future release. [2] Finally, again similar to the EETs, EDPs are subject to inactivation by being further metabolized by beta oxidation. [17]

Clinical significance

EDPs have not be studied nearly as well as the EETs. This is particularly the case for animal studies into their potential clinical significance. In comparison to a selection of the many activities attributed to the EETs (see Epoxyeicosatrienoic acid), animal studies reported to date find that certain EDPs (16,17-EDP and 19,20-EDP have been most often examined) are: 1) more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or at least equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that EDPs inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems. [1] [3] [16] [17] As indicated in the Metabolism section, consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans and in humans is by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids. Hence, the metabolism of DHA to EDPs (and EPA to EEQs) may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids. [1] [13] [17]

Related Research Articles

<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. Eicosanoids may also act as endocrine agents to control the function of distant cells.

<span class="mw-page-title-main">CYP2E1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

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

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, soluble epoxide hydrolase (sEH), also termed epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.

<span class="mw-page-title-main">CYP1A1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.

In biochemistry, docosanoids are signaling molecules made by the metabolism of twenty-two-carbon fatty acids (EFAs), especially the omega-3 fatty acid, Docosahexaenoic acid (DHA) by lipoxygenase, cyclooxygenase, and cytochrome P450 enzymes. Other docosanoids are metabolites of n-3 docosapentaenoic acid, n-6 DHA (i.e. 4Z,7Z,10Z,13Z,16Z-docosahexaenoic acid, and docosatetraenoic acid. Prominent docosanoid metabolites of DHA and n-3 DHA are members of the specialized proresolving mediator class of polyunsaturated fatty acid metabolites that possess potent anti-inflammation, tissue healing, and other activities.

<span class="mw-page-title-main">CYP2J2</span> Gene of the species Homo sapiens

Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.

<span class="mw-page-title-main">CYP2C18</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.

<span class="mw-page-title-main">CYP4A11</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.

<span class="mw-page-title-main">CYP2S1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2S1 is a protein that in humans is encoded by the CYP2S1 gene. The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substrate of the CYP epoxylgenases is arachidonic acid. This polyunsaturated fatty acid is metabolized by cyclooxygenases to various prostaglandin, thromboxane, and prostacyclin metabolites in what has been termed the first pathway of eicosanoid production; it is also metabolized by various lipoxygenases to hydroxyeicosatetraenoic acids and leukotrienes in what has been termed the second pathway of eicosanoid production. The metabolism of arachidonic acid to epoxyeicosatrienoic acids by the CYP epoxygenases has been termed the third pathway of eicosanoid metabolism. Like the first two pathways of eicosanoid production, this third pathway acts as a signaling pathway wherein a set of enzymes metabolize arachidonic acid to a set of products that act as secondary signals to work in activating their parent or nearby cells and thereby orchestrate functional responses. However, none of these three pathways is limited to metabolizing arachidonic acid to eicosanoids. Rather, they also metabolize other polyunsaturated fatty acids to products that are structurally analogous to the eicosanoids but often have different bioactivity profiles. This is particularly true for the CYP epoxygenases which in general act on a broader range of polyunsaturated fatty acids to form a broader range of metabolites than the first and second pathways of eicosanoid production. Furthermore, the latter pathways form metabolites many of which act on cells by binding with and thereby activating specific and well-characterized receptor proteins; no such receptors have been fully characterized for the epoxide metabolites. Finally, there are relatively few metabolite-forming lipoxygenases and cyclooxygenases in the first and second pathways and these oxygenase enzymes share similarity between humans and other mammalian animal models. The third pathway consists of a large number of metabolite-forming CYP epoxygenases and the human epoxygenases have important differences from those of animal models. Partly because of these differences, it has been difficult to define clear roles for the epoxygenase-epoxide pathways in human physiology and pathology.

<span class="mw-page-title-main">Epoxide hydrolase 2</span> Protein-coding gene in the species Homo sapiens

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding diols. A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia.

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

Coronaric acid (leukotoxin or leukotoxin A) is a mono-unsaturated, epoxide derivative of the di-saturated fatty acid, linoleic acid (i.e. 9(Z),12(Z) octadecadienoic acid). It is a mixture of the two optically active isomers of 12(Z) 9,10-epoxy-octadecenoic acid. This mixture is also termed 9,10-epoxy-12Z-octadecenoic acid or 9(10)-EpOME and when formed by or studied in mammalians, leukotoxin.

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

Epoxyeicosatetraenoic acids are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

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

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  6. ↑ Fer, M; Dréano, Y; Lucas, D; Corcos, L; Salaün, J. P.; Berthou, F; Amet, Y (2008). "Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450". Archives of Biochemistry and Biophysics. 471 (2): 116–25. doi:10.1016/j.abb.2008.01.002. PMID   18206980.
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  9. ↑ Xu, M; Ju, W; Hao, H; Wang, G; Li, P (2013). "Cytochrome P450 2J2: Distribution, function, regulation, genetic polymorphisms and clinical significance". Drug Metabolism Reviews. 45 (3): 311–52. doi:10.3109/03602532.2013.806537. PMID   23865864. S2CID   22721300.
  10. ↑ Kim HS, Moon SJ, Lee SE, Hwang GW, Yoo HJ, Song JW (May 2021). "The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis". Exp Mol Med. 53 (5): 864–874. doi:10.1038/s12276-021-00618-7. PMC   8178404 . PMID   33990688.
  11. ↑ Gross GJ, Falck JR, Gross ER, Isbell M, Moore J, Nithipatikom K (October 2005). "Cytochrome P450 and arachidonic acid metabolites: role in myocardial ischemia/reperfusion injury revisited". Cardiovasc Res. 68 (1): 18–25. doi:10.1016/j.cardiores.2005.06.007. PMID   15993870.
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