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. 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,17R-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] [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 19,20-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] [ failed verification ] 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. 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">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. They are nonclassic eicosanoids.

<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 (DPA), n-6 DPA, and docosatetraenoic acid. Prominent docosanoid metabolites of DPA and n-3 DHA are members of the specialized pro-resolving mediators 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

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<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.

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

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<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.

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Jorge H. Capdevila is an American biochemist and professor emeritus of medicine at Vanderbilt University Medical School. He was named fellow of the American Heart Association in 2002 and received the 2004 American Heart Association's "Novartis Excellence Award for Hypertension Research" for his contributions to our understanding of the molecular basis of hypertension. Capdevila's identification of roles for Cytochrome P450 (P450) in the metabolism of arachidonic acid (AA) and of the physiological and pathophysiological importance of these enzymes and their products were recognized in a special section honoring him at the 14th International Winter Eicosanoid Conference (2012). Capdevila received an "Outstanding Achievement Award" from the Eicosanoid Research Foundation at their 15th International Bioactive Lipid Conference (2017),.

References

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