Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain

omega-3 fatty acid Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lin ...

(DHA). Cell types that express certain cytochrome P450 (CYP)

epoxygenase Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP P450 or just CYP) enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substr ...

s metabolize

polyunsaturated fatty acid Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...

's (PUFAs) by converting one of their double bonds to an

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain

omega-6 fatty acid Omega-6 fatty acids (also referred to as ω-6 fatty acids or ''n''-6 fatty acids) are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the ''n''-6 position, that is, the sixth bond, counting from ...

, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid,

eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...

(EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides (see

) 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 (chemistry) In chemistry the descriptor vicinal (from Latin ''vicinus'' = neighbor), abbreviated ''vic'', describes any two functional groups bonded to two adjacent carbon atoms (i.e., in a 1,2-relationship). Relation of atoms in a molecule For example, th ...

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 Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation in the b ...

Structure

EDPs are

eicosapentaenoic acid metabolites of DHA. DHA has 6 cis (see Cis–trans isomerism)

Double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betwee ...

s 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, section on position isomerism (regioisomerism)). A given epoxygenase may therefore convert DHA to 4,5-EDP (i.e. 4,5-epoxy-7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-DPA), 7,8-EDP (i.e. 7,8-epoxy-4''Z'',10''Z'',13''Z'',16''Z'',19''Z''-DPA), 10,11-EDP (i.e. 10,11-epoxy-4''Z'',7''Z'',13''Z'',16''Z'',19''Z''-DPA), 13,14-EDP (i.e. 13,14-epoxy-4''Z'',7''Z'',10''Z'',16''Z'',19''Z''-DPA), 16,17-EDP (i.e. 16,17-epoxy-4''Z'',7''Z'',10''Z'',13''Z'',19''Z''-DPA, or 19,20-EDP (i.e. 19,20-epoxy-4''Z'', 7''Z'',10''Z'',13''Z'',16''Z''-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, 16''R'',17''S''-EDP and 16''S'',17''S''-EDP. The 4,5-EDP metabolite is unstable and generally not detected among the EDP formed by cells.

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 Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-cha ...

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

CYP2J2 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 d ...

, and possibly

CYP2S1 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. Expression CYP2S1 is ...

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

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. CYP1A1,

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), 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. Function ...

CYP2C18 Cytochrome P450 2C18 is a protein that in humans is encoded by the ''CYP2C18'' gene. Function This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactio ...

CYP2E1 Cytochrome P450 2E1 (abbreviated CYP2E1, ) 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, includ ...

, CYP4A11, CYP4F8, and CYP4F12 also metabolize DHA to EDPs. 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

metabolizes DHA to 7,8-EDP, 10,11-EDP, and 19,20-EDP isomers CYP2J2 metabolizes DHA to EPAs, principally 19,20-EPA, at twice the rate that it metabolizes arachidonic acid to EETs. In addition to the cited CYP's, CYP4A11, CYP4F8, CYP4F12, CYP1A1,

, and

, 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). 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. 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. 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.

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 C 3.2.2.10. to form their corresponding

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. 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''),1y(''S'')-dihydroxy-DPA. 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 Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...

and

paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...

signaling agents, respectively. In addition to the sEH pathway, EDPs, similar to the EETs, may be acylated into phospholipids in an

Acylation In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent. Because they form a strong electrophile when treated with ...

-like reaction; this pathway may serve to limit the action of EETs or store them for future release. Finally, again similar to the EETs, EDPs are subject to inactivation by being further metabolized b

Beta oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cyc ...

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. 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.

References

{{Reflist Metabolic pathways Cytochrome P450 Docosanoids Fatty acids Epoxides Cell biology Immunology Inflammations Blood pressure Human physiology Animal physiology