Epoxygenase

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Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP450 or just CYP) enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities. [1]

Contents

The most thoroughly-studied substrate of the CYP epoxygenases is the PUFA arachidonic acid (AA). Eicosanoids are created from AA in three pathways:

  1. Cyclooxygenases metabolize AA to various prostaglandin, thromboxane, and prostacyclin metabolites.
  2. Lipoxygenases metabolize AA to hydroxyeicosatetraenoic acids (e.g. 5-HETE or 12-HETE) and leukotrienes (e.g. leukotriene B4 or leukotriene C4).
  3. CYP epoxygenases metabolize AA to epoxyeicosatrienoic acids (EETs). [2]

Like the first two pathways, the third acts as a signaling pathway wherein the eicosatrienoic acid epoxide products work as secondary signals to activate their parent or nearby cells and thereby orchestrate functional responses. However, these enzymes are not limited to metabolizing AA to these particular eicosanoids. Rather, they act broadly across other PUFAs and produce a range of products that are structurally analogous to the eicosanoids but often with different bioactivity profiles. This is particularly true of the CYP epoxygenases.

While there are specific and well-characterized receptor proteins which metabolites from the first pathways are known to activate, no such receptors have been fully characterized for the epoxide metabolites. Furthermore, there are relatively few lipoxygenases and cyclooxygenases in the first and second pathways that form metabolites. There are a much larger number of metabolite-forming CYP epoxygenases, and they have important differences in mammalian animal models that make the research inapplicable to human biology. Thus, it has been difficult to define clear roles for the epoxygenase-epoxide pathways in human physiology and pathology.

CYP epoxygenases

The cytochrome P450 (CYP) superfamily of membrane-bound (typically endoplasmic reticulum-bound) enzymes contain a heme cofactor and therefore are hemoproteins. The superfamily comprises more than 11,000 genes categorized into 1,000 families that are distributed broadly throughout bacteria, archaea, fungi, plants, animals, and even viruses. The CYP enzymes metabolize an enormously large variety of small and large molecules including foreign chemical substances, i.e. xenobiotics and pharmaceuticals, as well as a diversity of endogenously-formed substances such as various steroids, vitamin D, bilirubin, cholesterol, and fatty acids. [2] Humans have 57 putatively active CYP genes and 58 CYP pseudogenes of which only a few are polyunsaturated fatty acid (PUFA) epoxygenases, i.e. enzymes with the capacity to attach atomic oxygen to the carbon–carbon double bonds of long chain PUFA to form their corresponding epoxides. [2] These CYP epoxygenases represent a family of enzymes that consists of several members of the CYP1 and CYP2 subfamilies. The metabolism of the straight chain 20-carbon polyunsaturated fatty eicosatetraenoic acid arachidonic acid (AA) by certain CYP epoxygenases is a good example of their action. AA has four cis-configured double bonds (see Cis–trans isomerism) located between carbons 5-6, 8-9, 11-12, and 14-15 double bonds. (The cis configuration is termed Z in the IUPAC chemical nomenclature used here.) It is therefore 5Z,8Z,11Z,14Z-eicosatetraenoic acid. Certain CYP epoxygenases attack these double bonds to form their respective eicosatrienoic acid epoxide regioisomers. The products are therefore 5,6-EET (i.e. 5,6-epoxy-8Z,11Z,14Z-eicosatetraenoic acid), 8,9-EET (i.e. 8,9-epoxy-5Z,11Z,14Z-eicosatetraenoic acid), 11,12-EET (i.e. 11,12-epoxy-5Z,8Z,14Z-eicosatetraenoic acid), and/or 14,15-EET (i.e. 14,15-epoxy-5Z,8Z,11Z-eicosatetraenoic acid, the structure of which is illustrated in the attached figure). Note that the eicosatetraenoate substrate loses one double bond to become an eicosatrienoic acid with three double bonds and that the epoxygenases typically form a mixture of R/S enantiomers at the attacked double bond position. Thus, the CYP epoxygenases which attack AA's double bond between carbon 14 and 15 form a mixture of 14R,15S-ETE and 14S,15R-ETE. [1] However, each CYP epoxygenase often shows preferences in the position of the double bond on which they act, partial selectivity in the R/S enantiomer ratios that they make at each double bond position, and different double bond position preferences and R/S selectivity ratios with different PUFA substrates. [3] Finally, the product epoxides are short-lived in cells, generally existing for only several seconds before being converted by a soluble epoxide hydrolase (also termed epoxide hydrolase 2 or sEH) to their corresponding dihydroxy-eicosatetraenoic acid (diHETE) products, e.g. 14,15-EpETE rapidly becomes a mixture of 14(S),15(R)-diHETE and 14(R),15(S)-diHETE. [1] [ failed verification ] Although there are exceptions, the diHETE products are generally far less active than their epoxide precursors; the sEH pathway is therefore regarded as an inactivating pathway which functions to limit epoxide activity. [1] [4]

The catalytic activity of endoplasmic reticulum-bound cytochrome P450 enzymes, including the epoxygenases, depends upon cytochrome P450 reductase (POR); it transfers electrons to, and thereby regenerates the activity of, the CYPs. [2] The human gene that expresses POR is highly polymorphic; many of the polymorphic variant PORs cause significant decreases or increases in the activity of the CYPs, including the epoxygenases. [2] [5]

Scores of drugs have been shown to either inhibit or induce one or more of the CYP epoxygenases; [2]

CYP epoxygenase substrates and products

The most studied substrate of the CYP epoxygenases is the omega−6 fatty acid arachidonic acid. However, the CYP epoxygenases also metabolize other omega−6 fatty acids such as linoleic acid and the omega−3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The distinction between the omega−6 and omega−3 fatty acid substrates is important because omega−3 fatty acid metabolites can have lesser or different activities than omega−6 fatty acid metabolites; furthermore, they compete with the omega−6 fatty acids for the CYP epoxygenases, thereby reducing the production of omega−6 fatty acid metabolites. [1] [6] The human CYP P450 enzymes identified to have epoxygenase activity on one or more PUFAs include CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, CYP2S1, CYP3A4, CYP4F2, CYP4F3A, CYP4F3B, CYP4A11, CYP4F8, and CYP4F12. [3] [7] [8] [9] CYP2C8 and CYP2C9 form particularly large amounts of superoxide anion (chemical formula O−
2) during their metabolism of polyunsaturated fatty acids; this reactive oxygen species is toxic to cells and may be responsible for some of the activities ascribed to the epoxides made by the two CYPs. [10]

Omega−6 fatty acids

Arachidonic acid

In humans, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 isoforms metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) as defined using recombinant CYPs in an in vitro microsome assay. [2] [1] [6] [8] [10] Most of these CYPs preferentially form 14,15-ETE, somewhat lower levels of 11,12-EET, and far lower, trace, or undetectable levels of 8,9-ETE and 4,5-ETE. There are exceptions to this rule with, for example, CYPE1 forming 14,15-EET almost exclusively, CYP2C19 forming 8,9-EET at slightly higher levels than 14,15-EET, and CYP3A4 forming 11,12-EET at slightly higher levels than 14,15-ETE. [1] [11] 14,15-EET and 11,12-EET are the major EETs produced by mammalian, including human, tissues. [1] The activities and clinical significance of the EETs are given on the epoxyeicosatrienoic acid page.

CYP2C9, CYP2JP, and possibly the more recently characterized CYP2S1 appear to be the main producers of the EETs in humans, with CYPP2C9 being the main unsaturated fatty acid epoxide producer in vascular endothelial cells, and CYP2J2 being highly expressed (although less catalytically active than CYP2C9) particularly in heart muscle but also in kidneys, pancreas, lung, and brain. [11] CYP2S1 is expressed in macrophages, liver, lung, intestine, and spleen; is abundant in human and mouse atherosclerosis (i.e. atheroma) plaques as well as inflamed tonsils; [10] and, in addition to forming epoxides of AA (and other PUFAs), CYP2S1 metabolizes prostaglandin G2 and prostaglandin H2 to 12-hydroxyheptadecatrienoic acid (12-HHT). Possibly because of metabolizing and thereby inactivating the prostaglandins and/or because forming the bioactive metabolite, 12-HHT acid, rather than EETs, CYP2S1 may act to inhibit the function of monocytes and thereby limit inflammation as well as other immune responses. [8] [10]

CYP2C8, CYP2C19, and CYP2J2 are also implicated in converting AA to epoxides in humans. [11]

Linoleic acid

CYP2C9 and CYP2S1 are known to, and many or all of the other CYPs that act on arachidonic acid are thought to, metabolize the 18 carbon essential fatty acid 9(Z),12(Z)-octadecadienoic acid, i.e. linoleic acid, at its 12,13 carbon–carbon double bonds to form (+) and (-) epoxy optical isomers viz., the 12S,13R-epoxy-9(Z)-octadecenoic and 12R,13S-epoxy-9(Z)-octadecenoic acids; this set of optical isomers is also termed vernolic acid, linoleic acid 12,13-oxide, and isoleukotoxin. CYPC2C9 is known and the other arachidonic acid-metabolizing CYPs are thought to likewise attack linoleic acid at its 9,10 carbon–carbon double bond to form 9S,10R-epoxy-12(Z)-octadecenoic and 9R,10S-epoxy-12(Z)-octadecenoic acid optical isomers; this set of optical isomers is also termed coronaric acid, linoleic acid 9,10-oxide, and leukotoxin. [1] [12] [13] These linoleic acid-derived leukotoxin and isoleukotoxin sets of optical isomers possess activities similar to those of other molecules called leukotoxins, such as the pore-forming leukotoxin family of RTX toxin virulence factor proteins secreted by gram-negative bacteria, e.g. Aggregatibacter actinomycetemcomitans and Escherichia coli . That is, they are toxic to leukocytes as well as many other cell types and when injected into rodents produce multiple organ failure and respiratory distress. [1] [14] [15] [16] These effects appear due to the conversion of leukotoxin to its dihydroxy counterparts, 9R,10R- and 9S,10S-dihydroxy-12(Z)-octadecenoic acids, and isoleukotoxin to its 12R,13R- and 12S,13S-dihydroxy-9(Z)-octadecenoic acid counterparts by soluble epoxide hydrolase. [17] Some studies suggest but have not proven that leukotoxin and isoleukotoxin, acting primarily if not exclusively through their respective dihydroxy counterparts, are responsible for or contribute to multiple organ failure, respiratory distress, and certain other cataclysmic diseases in humans. [15] [18] [19]

Adrenic acid

Adrenic acid or 7(Z),10(Z),13(Z),16(Z)-docosatetraenoic acid, an abundant fatty acid in the adrenal gland, kidney, vasculature, and early human brain, is metabolized primarily to 7(Z),10(Z),13(Z)-16,17-epoxy-docosatrienoic acid and smaller amounts of its 7,8-, 10,11-, and 13,14-epoxy-docosatrienoic acids by bovine coronary arteries and adrenal zona glomerulosa cells through the apparent action of an unidentified CYP epoxygenase(s); the sEH-dependent metabolism of these epoxides to 7,8-, 10,11-, and 13,14-dihydroxy-docosatrienoic acids relaxes pre-contracted coronary and adrenal gland arteries suggesting that the dihydroxy metabolites may act as vascular endothelium-derived relaxing factors. [20]

Omega−3 fatty acids

Eicosapentaenoic acid

5(Z),8(Z),11(Z),14(Z),17(Z)-eicosapentaenoic acid (EPA) is metabolized by the same CYP epoxygenases that metabolize arachidonic acid primarily to 17,18-epoxy-5(Z),8(Z),11(Z),14(Z)-eicosatetraenoic acid and usually far smaller or undetectable amounts of EPA's 5,6-, 8,9-, 11,12-, or 14,15-epoxides; however, CYP2C9 metabolizes EPA primarily to 14,15-epoxy-5(Z),8(Z),11(Z),17(Z)-eicosatetraenoic acid, CYP2C11 forms appreciable amounts of this 14,15-epoxide in addition to the 17,18-epoxide, and CYP2C18 forms appreciable amounts of the 11,12 epoxide (11,12-epoxy-5(Z),8(Z),14(Z),17(Z)-eicosatetraenoic acid) in addition to the 17,18-epoxide. Furthermore, CYP4A11, CYP4F8, and CYP4F12, which are CYP monooxygenase rather than CYP epoxygenase in that they metabolize arachidonic acid to monohydroxy eicosatetraenoic acid products (see 20-Hydroxyeicosatetraenoic acid), i.e. 19-hydroxy- and/or 18-hydroxy-eicosatetraenoic acids, takes on epoxygenase activity in converting EPA primarily to its 17,18-epoxy metabolite (see Epoxyeicosatetraenoic acid). [7]

Docosahexaenoic acid

4(Z),7(Z),10(Z),13(Z),16(Z),19(Z)-docosahexaenoic acid (DHA) is metabolized by the same CYP epoxygenases that metabolize arachidonic acid to form epoxide-containing docosapentaenoic acid products, particularly 19,20-epoxy-4(Z),7(Z),10(Z),13(Z),16(Z)-docosapentenoic acid. [21] These docosapentaenoic acid epoxides or epoxydocosapentaenoic acids (EDPs) have a somewhat different set of activities than, and thereby may serve in part as counterpoises to, the EETs; EDPs may also be responsible for some the beneficial effects attributed to omega−fatty acid-rich foods such as fish oil (see Epoxydocosapentaenoic acid). [22]

α-Linolenic acid

The 18 carbon essential fatty acid, α-linolenic acid or 9(Z),12(Z),15(Z)-octadecatrienoic acid, is metabolized primarily to 9(Z),12(Z)-15,16-epoxy-octadecadienoic acid, but also to smaller amounts of its 9,10- and 12,13-epoxides in the serum, liver, lung, and spleen of mice treated with a drug that increases the expression of CYP1A1, CYP1A2 and/or CYP1B1. [20] [23] These epoxides are also found in the plasma of humans, and their levels greatly increase in subjects given an α-linolenic acid-rich diet. [24]

Genetic polymorphism in CYP epoxygenases

Human CYP epoxygenase genes come in many single nucleotide polymorphism (SNP) variants, some of which code for epoxygenase products with altered activity. Investigation into the impact of these variants on the bearers' health (i.e. phenotype) is an invaluable area of research which offers the opportunity to define the function of the epoxygenases and their polyunsaturated fatty acid (PUFA) metabolites in humans. However, SNP variants that cause altered PUFA metabolism may also cause altered metabolism of their other substrates, i.e. diverse xenobiotic (e.g. NSAID) and endobiotic (e.g. the primary female sex hormone, estradiol) compounds: the latter effects may lead to clinical manifestations that overshadow any manifestations resulting from changes in PUFA metabolism.

The most common SNP epoxygenase variants are as follows.

Genetic polymorphism in cytochrome P450 reductase

As indicated above, cytochrome P450 reductase (POR) is responsible for regenerating the activity of CYPs including the epoxygenases. Several genetic variants of the human POR gene impact epoxygenase activity. For example, POR missense mutations A287P [43] and R457H [44] lead to reductions in the activity of CYP2C19 and CYP2C9, respectively, whereas A503V [45] and Q153R [46] missense mutations lead to small increases in the activity of CYP2C9. [2] While these and other POR genetic variants have not yet been associated with epoxygenase-related disease, they contribute to the marked variability in the activity of the epoxygenases between individuals.

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">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">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 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 proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

<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.

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

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

<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.

<span class="mw-page-title-main">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

<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-unsaturated 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 (for Epoxy-Octadeca-MonoEnoic acid) and when formed by or studied in mammalians, leukotoxin.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids 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. 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. 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 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.

<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.

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),.

In biochemistry, cytochrome P450 enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, and archaea, as well as in viruses. As of 2018, more than 300,000 distinct CYP proteins are known.

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  9. ↑ Bishop-Bailey, D; Thomson, S; Askari, A; Faulkner, A; Wheeler-Jones, C (2014). "Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism". Annual Review of Nutrition. 34: 261–79. doi:10.1146/annurev-nutr-071813-105747. PMID   24819323.
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  11. 1 2 3 Yang, L; Mäki-Petäjä, K; Cheriyan, J; McEniery, C; Wilkinson, I. B. (2015). "The role of epoxyeicosatrienoic acids in the cardiovascular system". British Journal of Clinical Pharmacology. 80 (1): 28–44. doi:10.1111/bcp.12603. PMC   4500322 . PMID   25655310.
  12. ↑ Draper, A. J.; Hammock, B. D. (2000). "Identification of CYP2C9 as a human liver microsomal linoleic acid epoxygenase". Archives of Biochemistry and Biophysics. 376 (1): 199–205. doi:10.1006/abbi.2000.1705. PMID   10729206.
  13. ↑ Konkel, A; Schunck, W. H. (2011). "Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 210–22. doi:10.1016/j.bbapap.2010.09.009. PMID   20869469.
  14. ↑ Moran, J. H.; Weise, R; Schnellmann, R. G.; Freeman, J. P.; Grant, D. F. (1997). "Cytotoxicity of linoleic acid diols to renal proximal tubular cells". Toxicology and Applied Pharmacology. 146 (1): 53–9. doi:10.1006/taap.1997.8197. PMID   9299596.
  15. 1 2 Greene, J. F.; Hammock, B. D. (1999). "Toxicity of Linoleic Acid Metabolites". Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 4. Advances in Experimental Medicine and Biology. Vol. 469. pp. 471–7. doi:10.1007/978-1-4615-4793-8_69. ISBN   978-1-4613-7171-7. PMID   10667370.
  16. ↑ Linhartová, I; Bumba, L; Mašín, J; Basler, M; Osička, R; Kamanová, J; Procházková, K; Adkins, I; Hejnová-Holubová, J; Sadílková, L; Morová, J; Sebo, P (2010). "RTX proteins: A highly diverse family secreted by a common mechanism". FEMS Microbiology Reviews. 34 (6): 1076–112. doi:10.1111/j.1574-6976.2010.00231.x. PMC   3034196 . PMID   20528947.
  17. ↑ Greene, J. F.; Newman, J. W.; Williamson, K. C.; Hammock, B. D. (2000). "Toxicity of epoxy fatty acids and related compounds to cells expressing human soluble epoxide hydrolase". Chemical Research in Toxicology. 13 (4): 217–26. doi:10.1021/tx990162c. PMID   10775319.
  18. ↑ Zheng, J; Plopper, C. G.; Lakritz, J; Storms, D. H.; Hammock, B. D. (2001). "Leukotoxin-diol: A putative toxic mediator involved in acute respiratory distress syndrome". American Journal of Respiratory Cell and Molecular Biology. 25 (4): 434–8. doi:10.1165/ajrcmb.25.4.4104. PMID   11694448. S2CID   27194509.
  19. ↑ Edwards, L. M.; Lawler, N. G.; Nikolic, S. B.; Peters, J. M.; Horne, J; Wilson, R; Davies, N. W.; Sharman, J. E. (2012). "Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion". The Journal of Lipid Research. 53 (9): 1979–86. doi: 10.1194/jlr.P027706 . PMC   3413237 . PMID   22715155.
  20. 1 2 Westphal C, Konkel A, Schunck WH (2015). "Cytochrome P450 Enzymes in the Bioactivation of Polyunsaturated Fatty Acids and Their Role in Cardiovascular Disease". In Hrycay EG, Bandiera SM (eds.). Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450. Advances in Experimental Medicine and Biology. Vol. 851. pp. 151–87. doi:10.1007/978-3-319-16009-2_6. ISBN   978-3-319-16008-5. PMID   26002735.
  21. ↑ Wagner, K; Inceoglu, B; Hammock, B. D. (2011). "Soluble epoxide hydrolase inhibition, epoxygenated fatty acids and nociception". Prostaglandins & Other Lipid Mediators. 96 (1–4): 76–83. doi:10.1016/j.prostaglandins.2011.08.001. PMC   3215909 . PMID   21854866.
  22. ↑ Zhang, G; Kodani, S; Hammock, B. D. (2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–23. doi:10.1016/j.plipres.2013.11.003. PMC   3914417 . PMID   24345640.
  23. ↑ Yang, J; Solaimani, P; Dong, H; Hammock, B; Hankinson, O (2013). "Treatment of mice with 2,3,7,8-Tetrachlorodibenzo-p-dioxin markedly increases the levels of a number of cytochrome P450 metabolites of omega-3 polyunsaturated fatty acids in the liver and lung". The Journal of Toxicological Sciences. 38 (6): 833–6. doi:10.2131/jts.38.833. PMC   4068614 . PMID   24213002.
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  42. ↑ Painter, J. N.; Nyholt, D. R.; Krause, L; Zhao, Z. Z.; Chapman, B; Zhang, C; Medland, S; Martin, N. G.; Kennedy, S; Treloar, S; Zondervan, K; Montgomery, G. W. (2014). "Common variants in the CYP2C19 gene are associated with susceptibility to endometriosis". Fertility and Sterility. 102 (2): 496–502.e5. doi:10.1016/j.fertnstert.2014.04.015. PMC   4150687 . PMID   24796765.
  43. ↑ "Mutation overview page NTNG1 - p.A287P ( Substitution - Missense)".
  44. ↑ "Mutation overview page ZNF439 - p.R457H ( Substitution - Missense)".
  45. ↑ "Rs1057868 - SNPedia".
  46. ↑ "Mutation overview page SLC22A2 - p.Q153R ( Substitution - Missense)".
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