Eicosanoid

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File:Eicosanoid synthesis.svg
Pathways in biosynthesis of eicosanoids from arachidonic acid: there are parallel paths from EPA & DGLA.

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.<ref name="tmbp">Template:Cite web</ref><ref>Template:Cite web</ref>

There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and eoxins.<ref name=tmbp/> For each subfamily, there is the potential to have at least 4 separate series of metabolites, two series derived from the ω−6 PUFAs arachidonic and dihomo-gamma-linolenic acids, one series derived from the ω−3 PUFA eicosapentaenoic acid, and one series derived from the ω−9 PUFA mead acid. This subfamily distinction is important. Mammals, including humans, are unable to convert ω−6 into ω−3 PUFA. In consequence, tissue levels of the ω−6 and ω−3 PUFAs and their corresponding eicosanoid metabolites link directly to the amount of dietary ω−6 versus ω−3 PUFAs consumed.<ref name="pmid18769551">Template:Cite journal</ref> Since certain of the ω−6 and ω−3 PUFA series of metabolites have almost diametrically opposing physiological and pathological activities, it has often been suggested that the deleterious consequences associated with the consumption of ω−6 PUFA-rich diets reflects excessive production and activities of ω−6 PUFA-derived eicosanoids, while the beneficial effects associated with the consumption of ω−3 PUFA-rich diets reflect the excessive production and activities of ω−3 PUFA-derived eicosanoids.<ref name="DeCaterina">Template:Cite journal</ref><ref name="Funk">Template:Cite journal</ref><ref name="Piomelli">Template:Cite journal</ref><ref name="Soberman">Template:Cite journal</ref> In this view, the opposing effects of ω−6 PUFA-derived and ω−3 PUFA-derived eicosanoids on key target cells underlie the detrimental and beneficial effects of ω−6 and ω−3 PUFA-rich diets on inflammation and allergy reactions, atherosclerosis, hypertension, cancer growth, and a host of other processes.

Nomenclature

Template:See also

Fatty acid sources

"Eicosanoid" (Template:Ety) is the collective term<ref name="Beare">Template:Cite web</ref> for straight-chain PUFAs (polyunsaturated fatty acids) of 20 carbon units in length that have been metabolized or otherwise converted to oxygen-containing products. The PUFA precursors to the eicosanoids include:

  • Arachidonic acid (AA), i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid is an ω−6 fatty acid with four double bonds in the cis configuration (denoted Z in E–Z notation), each located between carbons 5-6, 8-9, 11-12, and 14-15 (see carbon numbering).
  • Adrenic acid (AdA), i.e. 7Z,10Z,13Z,16Z-docosatetraenoic acid, is an ω−6 fatty acid with four cis double bonds, each located between carbons 7-8, 10-11, 13-14, and 16-17.
  • Eicosapentaenoic acid (EPA), i.e. 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid is an ω−3 fatty acid with five cis double bonds, each located between carbons 5-6, 8-9, 11-12, 14-15, and 17-18.
  • Dihomo-gamma-linolenic acid (DGLA), i.e. 8Z,11Z,14Z-eicosatrienoic acid is an ω−6 fatty acid with three cis double bonds, each located between carbons 8-9, 11-12, and 14-15.
  • Mead acid, i.e. 5Z,8Z,11Z-eicosatrienoic acid, is an ω−9 fatty acid containing three cis double bonds, each located between carbons 5-6, 8-9, and 11-12.

Abbreviation

A particular eicosanoid is denoted by a four-character abbreviation, composed of:

  • its two-letter abbreviation (LT, EX or PG, as described below),<ref>Prostacyclin—PGI—was previously classified as prostaglandin and retains its old PGI2 identifier.</ref>
  • one A-B-C sequence-letter,<ref name="CyberlipidP">Eicosanoids with different letters have placement of double-bonds and different functional groups attached to the molecular skeleton. Letters indicate roughly the order the eicosanoids were first described in the literature. For diagrams for PG [A–H] see Template:Cite web</ref>
  • A subscript or plain script number following the designated eicosanoid's trivial name indicates the number of its double bonds. Examples are:
    • The EPA-derived prostanoids have three double bonds (e.g. PGG3 or PGG3) while leukotrienes derived from EPA have five double bonds (e.g. LTB5 or LTB5).
    • The AA-derived prostanoids have two double bonds (e.g. PGG2 or PGG2) while their AA-derived leukotrienes have four double bonds (e.g. LTB4 or LTB4).
  • Hydroperoxy-, hydroxyl-, and oxo-eicosanoids possess a hydroperoxy (-OOH), hydroxy (-OH), or oxygen atom (=O) substituents link to a PUFA carbon by a single (-) or double (=) bond. Their trivial names indicate the substituent as: Hp or HP for a hydroperoxy residue (e.g. 5-hydroperooxy-eicosatraenoic acid or 5-HpETE or 5-HPETE); H for a hydroxy residue (e.g. 5-hydroxy-eicosatetraenoic acid or 5-HETE); and oxo- for an oxo residue (e.g. 5-oxo-eicosatetraenioic acid or 5-oxo-ETE or 5-oxoETE). The number of their double bonds is indicated by their full and trivial names: AA-derived hydroxy metabolites have four (i.e. 'tetra' or 'T') double bonds (e.g. 5-hydroxy-eicosatetraenoic acid or 5-HETE; EPA-derived hydroxy metabolites have five ('penta' or 'P') double bonds (e.g. 5-hydroxy-eicosapentaenoic acid or 5-HEPE); and DGLA-derived hydroxy metabolites have three ('tri' or 'Tr') double bonds (e.g. 5-hydroxy-eicosatrienoic acid or 5-HETrE).

The stereochemistry of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters (e.g. PGF2α versus PGF2β). For hydroperoxy and hydroxy eicosanoids an S or R designates the chirality of their substituents (e.g. 5S-hydroxy-eicosateteraenoic acid [also termed 5(S)-, 5S-hydroxy-, and 5(S)-hydroxy-eicosatetraenoic acid] is given the trivial names of 5S-HETE, 5(S)-HETE, 5S-HETE, or 5(S)-HETE). Since eicosanoid-forming enzymes commonly make S isomer products either with marked preference or essentially exclusively, the use of S/R designations has often been dropped (e.g. 5S-HETE is 5-HETE). Nonetheless, certain eicosanoid-forming pathways do form R isomers and their S versus R isomeric products can exhibit dramatically different biological activities.<ref name="pmid3191990">Template:Cite journal</ref> Failing to specify S/R isomers can be misleading. Here, all hydroperoxy and hydroxy substituents have the S configuration unless noted otherwise.

Classic eicosanoids

Current usage limits the term eicosanoid to:

Hydroxyeicosatetraenoic acids, leukotrienes, eoxins and prostanoids are sometimes termed "classic eicosanoids".<ref name="vandyke">Template:Cite journal</ref><ref name="Serhan">Template:Cite journal</ref><ref name="Anderle">Template:Cite journal</ref>

Nonclassic eicosanoids

In contrast to the classic eicosanoids, several other classes of PUFA metabolites have been termed 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'.<ref name="Evans">Template:Cite journal</ref><ref name="O">Template:Cite journal</ref><ref name="pmid11306946">Template:Cite journal</ref><ref name="pmid10477044">Template:Cite journal</ref> These included the following classes:

Metabolism of eicosapentaenoic acid to HEPEs, leukotrienes, prostanoids, and epoxyeicosatetraenoic acids as well as the metabolism of dihomo-gamma-linolenic acid to prostanoids and mead acid to 5(S)-hydroxy-6E,8Z,11Z-eicosatrienoic acid (5-HETrE), 5-oxo-6,8,11-eicosatrienoic acid (5-oxo-ETrE), LTA3, and LTC3 involve the same enzymatic pathways that make their arachidonic acid-derived analogs.

Biosynthesis

Eicosanoids typically are not stored within cells but rather synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane. These fatty acids must be released from their membrane sites and then metabolized initially to products which most often are further metabolized through various pathways to make the large array of products we recognize as bioactive eicosanoids.

Fatty acid mobilization

Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma, ischemia, other physical perturbations, attack by pathogens, or stimuli made by nearby cells, tissues, or pathogens such as chemotactic factors, cytokines, growth factors, and even certain eicosanoids. The activated cells then mobilize enzymes, termed phospholipases A2 (PLA2), capable of releasing ω−6 and ω−3 fatty acids from membrane storage. These fatty acids are bound in ester linkage to the SN2 position of membrane phospholipids; PLA2 act as esterases to release the fatty acid. There are several classes of PLA2 with type IV cytosolic PLA2 (cPLA2) appearing to be responsible for releasing the fatty acids under many conditions of cell activation. The cPLA2 act specifically on phospholipids that contain AA, EPA or GPLA at their SN2 position. cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.<ref name="University">Template:Cite web</ref>

Peroxidation and reactive oxygen species

Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O2). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidations proceed with high stereoselectivity (enzymatic oxidations are considered practically stereospecific).

Four families of enzymes initiate or contribute to the initiation of the catalysis of fatty acids to eicosanoids:

  • Cyclooxygenases (COXs): COX-1 and COX-2 initiate the metabolism of arachidonic acid to prostanoids that contain two double bonds, i.e. the prostaglandins (e.g. PGE2), prostacyclins (i.e. PGI2), and thromboxanes (e.g. TXA2). The two COX enzymes likewise initiate the metabolism of: a) Eicosapentaenoic acid, which has 5 double bonds compared to the 4 double bonds of arachidonic acid, to prostanoid, prostacyclin, and thromboxane products that have three double bonds, e.g. PGE3, PGI3, and TXA3 and b) Dihomo-γ-linolenic acid, which has three double bonds, to prostanoid, prostacyclin, and thromboxane products that have only one double bond, e.g. PGE1, PGI1, and TXA1.<ref name="pmid26374175">Template:Cite journal</ref>
  • Lipoxygenases (LOXs): 5-Lipoxygenase (5-LOX or ALOX5) initiates the metabolism of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) which then may be rapidly reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) or further metabolized to the leukotrienes (e.g. LTB4 and LTC4); 5-HETE may be oxidized to 5-oxo-eicosatetraenoic acid (5-oxo-ETE). In similar fashions, 15-lipoxygenase (15-lipoxygenase 1, 15-LOX, 15-LOX1, or ALOX15) initiates the metabolism of arachidonic acid to 15-HpETE, 15-HETE, eoxins, 8,15-dihydroxyeicosatetraenoic acid (i.e. 8,15-DiHETE), and 15-oxo-ETE and 12-lipoxygenase (12-LOX or ALOX12) initiates the metabolism of arachidonic acid to 12-HpETE, 12-HETE, hepoxilins, and 12-oxo-ETE. These enzymes also initiate the metabolism of; a) Eicosapentaenoic acid to analogs of the arachidonic acid metabolites that contain 5 rather than four double bonds, e.g. 5-hydroxyeicosapentaenoic acid (5-HEPE), LTB5, LTC5, 5-oxo-EPE, 15-HEPE, and 12-HEPE; b) The three double bond-containing dihomo-γ-linolenic acid to products that contain 3 double bonds, e.g. 8-hydroxy-eicosatrienoic acid (8-HETrE), 12-HETrE, and 15-HETrE (this fatty acid cannot be converted to leukotrienes); and the three double bond-containing mead acid (by ALOX5) to 5-hydroperoxy-eicosatrienoic acid (5-HpETrE), 5-HETrE, and 5-oxo-HETrE. In the most studied of these pathways, ALOX5 metabolizes eicosapentaenoic acid to 5-hydroperoxyeicosapentaenoic acid (5-HpEPE), 5-HEPE, and LTB5, and 5-oxo-EPE, all of which are less active than there arachidonic acid analogs. Since eicosapentaenoic acid competes with arachidonic acid for ALOX5, production of the eicosapentaenoate metabolites leads to a reduction in the eicosatetraenoate metabolites and therefore reduction in the latter metabolites' signaling.<ref name="pmid26374175" /><ref name="pmid25449650">Template:Cite journal</ref> The initial mono-hydroperoxy and mono-hydroxy products made by the aforementioned lipoxygenases have their hydroperosy and hydroxyl residues positioned in the S chiral configuration and are more properly termed 5S-HpETE, 5S-HETE, 12S-HpETE, 12S-HETE, 15S-HpETE and, 15S-HETE. ALOX12B (i.e. arachidonate 12-lipoxygenase, 12R type) forms R chirality products, i.e. 12R-HpETE and 12R-HETE. Similarly, ALOXE3 (i.e. epidermis-type lipoxygenase 3 or eLOX3) metabolizes arachidonic acid to 12R-HpETE and 12R-HETE; however these are minor products that this enzyme forms only under a limited set of conditions. ALOXE3 preferentially metabolizes arachidonic acid to hepoxilins.
  • Epoxygenases: these are cytochrome P450 enzymes which generate nonclassic eicosanoid epoxides derived from: a) Arachidonic acid viz., 5,6-epoxy-eicosatrienoic acid (5,6-EET), 8,9-EET, 11,12-EET, and 14,15-EET (see Epoxyeicosatrienoic acid); b) Eicosapentaenoic acid viz., 5,6,-epoxy-eicosatetraenoic acid (5,6-EEQ), 8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 17,18-EEQ (see Epoxyeicosatetraenoic acid); c) Dihomo-γ-linolenic acid viz., 8,9-epoxy-eicosadienoic acid (8,9-EpEDE), 11,12-EpEDE, and 14,15-EpEDE; and d) Adrenic acid viz., 7,8-epox-eicosatrienoic acid (7,8-EpETrR), 10,11-EpTrE, 13,14-EpTrE, and 16,17-EpETrE. All of these epoxides are converted, sometimes rapidly, to their dihydroxy metabolites, by various cells and tissues. For example, 5,6-EET is converted to 5,6-dihydroxy-eicosatrienoic acid (5,6-DiHETrE), 8,9-EEQ to 8,9-dihydroxy-eicosatetraenoic acid (8,9-DiHETE, 11,12-EpEDE to 11,12-dihydroxy-eicosadienoic acid (11,12DiHEDE), and 16,17-EpETrE to 16,17-dihydroxy-eicosatrienoic acid (16,17-DiETrE.<ref name="pmid26374175" />
  • Cytochrome P450 microsome ω hydroxylases: CYP4A11, CYP4A22, CYP4F2, and CYP4F3 metabolize arachidonic acid primarily to 20-hydroxyeicosatetraenoic acid (20-HETE) but also to 16-HETE, 17-HETE, 18-HETE, and 19-HETE; they also metabolize eicosapentaenoic acid primarily to 20-hydroxy-eicosapentaenoic acid (20-HEPE) but also to 19-HEPE.<ref name="pmid26374175" />

Two different enzymes may act in series on a PUFA to form more complex metabolites. For example, ALOX5 acts with ALOX12 or aspirin-treated COX-2 to metabolize arachidonic acid to lipoxins and with cytochrome P450 monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series resolvins (RvEs) (see Specialized pro-resolving mediators). When this occurs with enzymes located in different cell types and involves the transfer of one enzyme's product to a cell which uses the second enzyme to make the final product it is referred to as transcellular metabolism or transcellular biosynthesis.<ref name="pmid25218301">Template:Cite journal</ref>

The oxidation of lipids is hazardous to cells, particularly when close to the nucleus. There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases, and the phospholipases are tightly controlled—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms.<ref name="Soberman" />

Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.<ref name="Cyrus">Template:Cite journal</ref><ref name="Schewe">Template:Cite journal</ref> The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes that are biosynthetic for eicosanoids (e.g., glutathione-S-transferases, epoxide hydrolases, and carrier proteins) belong to families whose functions are involved largely with cellular detoxification. This suggests that eicosanoid signaling might have evolved from the detoxification of ROS.

The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus. PGs and LTs may signal or regulate DNA transcription there; LTB4 is ligand for PPARα.<ref name=Funk/> (See diagram at PPAR.)

Structures of selected eicosanoids
File:Prostaglandin E1.svg File:Thromboxane A2 acsv.svg File:Leukotriene B4.svg
Prostaglandin E1. The 5-member ring is characteristic of the class. Thromboxane A2. Oxygens
have moved into the ring. 		Leukotriene B4. Note the 3 conjugated double bonds.
File:Prostaglandin I2.png File:Leukotriene E4.svg
Prostacyclin I2. The second ring distinguishes it from the prostaglandins. Leukotriene E4, an example of a cysteinyl leukotriene.

Prostanoid pathways

Template:See also Both COX1 and COX2 (also termed prostaglandin-endoperoxide synthase-1 (PTGS1) and PTGS2, respectively) metabolize arachidonic acid by adding molecular O2 between carbons 9 and 11 to form an endoperoxide bridge between these two carbons, adding molecular O2 to carbon 15 to yield a 15-hydroperoxy product, creating a carbon-carbon bond between carbons 8 and 12 to create a cyclopentane ring in the middle of the fatty acid, and in the process making PGG2, a product that has two fewer double bonds than arachidonic acid. The 15-hydroperoxy residue of PGG2 is then reduced to a 15-hydroxyl residue thereby forming PGH2. PGH2 is the parent prostanoid to all other prostanoids. It is metabolized by (see diagram in Prostanoid): a) The prostaglandin E synthase pathway in which any one of three isozymes, PTGES, PTGES2, or PTGES3, convert PGH2 to PGE2 (subsequent products of this pathway include PGA2 and PGB2 (see Template:Slink); b) PGF synthase which converts PGH2 to PGF2α; c) Prostaglandin D2 synthase which converts PGH2 to PGD2 (subsequent products in this pathway include 15-dPGJ2 (see Cyclopentenone prostaglandin); d) Thromboxane synthase which converts PGH2 to TXA2 (subsequent products in this pathway include TXB2); and e) Prostacyclin synthase which converts PGH2 to PGI2 (subsequent products in this pathway include 6-keto-PGFα.<ref name="pmid25343148">Template:Cite journal</ref><ref name="pmid25541289">Template:Cite journal</ref> These pathways have been shown or in some cases presumed to metabolize eicosapentaenoic acid to eicosanoid analogs of the sited products that have three rather than two double bonds and therefore contain the number 3 in place of 2 attached to their names (e.g. PGE3 instead of PGE2).<ref name="pmid20558833">Template:Cite journal</ref>

The PGE2, PGE1, and PGD2 products formed in the pathways just cited can undergo a spontaneous dehydration reaction to form PGA2, PGA1, and PGJ2, respectively; PGJ2 may then undergo a spontaneous isomerization followed by a dehydration reaction to form in series Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2.<ref name="pmid21843512">Template:Cite journal</ref>

PGH2 has a 5-carbon ring bridged by molecular oxygen. Its derived PGS have lost this oxygen bridge and contain a single, unsaturated 5-carbon ring with the exception of thromboxane A2 which possesses a 6-member ring consisting of one oxygen and 5 carbon atoms. The 5-carbon ring of prostacyclin is conjoined to a second ring consisting of 4 carbon and one oxygen atom. And, the 5 member ring of the cyclopentenone prostaglandins possesses an unsaturated bond in a conjugated system with a carbonyl group that causes these PGs to form bonds with a diverse range of bioactive proteins (for more see the diagrams at Prostanoid).

Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways

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The enzyme 5-lipoxygenase (5-LO or ALOX5) converts arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which may be released and rapidly reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) by ubiquitous cellular glutathione-dependent peroxidases.<ref>Template:Cite journal</ref> Alternately, ALOX5 uses its LTA synthase activity to act convert 5-HPETE to leukotriene A4 (LTA4). LTA4 is then metabolized either to LTB4 by leukotriene A4 hydrolase or leukotriene C4 (LTC4) by either LTC4 synthase or microsomal glutathione S-transferase 2 (MGST2). Either of the latter two enzymes act to attach the sulfur of cysteine's thio- (i.e. SH) group in the tripeptide glutamate-cysteine-glycine to carbon 6 of LTA4 thereby forming LTC4. After release from its parent cell, the glutamate and glycine residues of LTC4 are removed step-wise by gamma-glutamyltransferase and a dipeptidase to form sequentially LTD4 and LTE4.<ref name="Rådmark_2015">Template:Cite journal</ref><ref name="pmid26066610">Template:Cite journal</ref> The decision to form LTB4 versus LTC4 depends on the relative content of LTA4 hydrolase versus LTC4 synthase (or glutathione S-transferase in cells; eosinophils, mast cells, and alveolar macrophages possess relatively high levels of LTC4 synthase and accordingly form LTC4 rather than or to a far greater extent than LTB4. 5-LOX may also work in series with cytochrome P450 oxygenases or aspirin-treated COX2 to form Resolvins RvE1, RvE2, and 18S-RvE1 (see Template:Slink).

The enzyme arachidonate 12-lipoxygenase (12-LO or ALOX12) metabolizes arachidonic acid to the S stereoisomer of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 12-hydroxyeicosatetraenoic acid (12-HETE) or further metabolized to hepoxilins (Hx) such as HxA3 and HxB.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

The enzymes 15-lipoxygenase-1 (15-LO-1 or ALOX15) and 15-lipoxygenase-2 (15-LO-2, ALOX15B) metabolize arachidonic acid to the S stereoisomer of 15-hydroperoxyeicosatetraenoic acid (15(S)-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 15-hydroxyeicosatetraenoic acid (15(S)-HETE).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The 15-lipoxygenases (particularly ALOX15) may also act in series with 5-lipoxygenase, 12-lipoxygenase, or aspirin-treated COX2 to form the lipoxins and epi-lipoxins or with P450 oxygenases or aspirin-treated COX2 to form Resolvin E3 (see Template:Slink).

A subset of cytochrome P450 (CYP450) microsome-bound ω hydroxylases metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) and 19-hydroxyeicosatetraenoic acid by an omega oxidation reaction.<ref name="Kroetz_2005">Template:Cite journal</ref>

Epoxyeicosanoid pathway

The human cytochrome P450 (CYP) epoxygenases, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 metabolize arachidonic acid to the non-classic epoxyeicosatrienoic acids (EETs) by converting one of the fatty acid's double bonds to its epoxide to form one or more of the following EETs, 14,15-ETE, 11,12-EET, 8,9-ETE, and 4,5-ETE.<ref name="ReferenceA">Template:Cite journal</ref><ref name="Apr 2014">Template:Cite journal</ref> 14,15-EET and 11,12-EET are the major EETs produced by mammalian, including human, tissues.<ref name="Apr 2014" /><ref>Template:Cite journal</ref><ref name="Pharmacol Ther 2014">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The same CYPs but also CYP4A1, CYP4F8, and CYP4F12 metabolize eicosapentaenoic acid to five epoxide epoxyeicosatetraenoic acids (EEQs) viz., 17,18-EEQ, 14,15-EEQ, 11,12-EEQ. 8,9-EEQ, and 5,6-EEQ.<ref>Template:Cite journal</ref>

Function, pharmacology, and clinical significance

The following table lists a sampling of the major eicosanoids that possess clinically relevant biological activity, the cellular receptors (see Cell surface receptor) that they stimulate or, where noted, antagonize to attain this activity, some of the major functions which they regulate (either promote or inhibit) in humans and mouse models, and some of their relevancies to human diseases.

Eicosanoid Targeted receptors Functions regulated Clinical relevancy
PGE2 PTGER1, PTGER2, PTGER3, PTGER4 inflammation; fever; pain perception; allodynia; parturition NSAIDs inhibit its production to reduce inflammation, fever, and pain; used to promote labor in childbirth; an abortifacient<ref name="pmid25541289" /><ref name="pmid17767353">Template:Cite journal</ref><ref name="pmid24941907">Template:Cite journal</ref>
PGD2 Prostaglandin DP1 receptor 1, Prostaglandin DP2 receptor allergy reactions; allodynia; hair growth NSAIDs may target it to inhibit allodynia and male-pattern hair loss<ref name="pmid25541289" /><ref name="pmid27424565">Template:Cite journal</ref><ref name="pmid22440736">Template:Cite journal</ref><ref name="pmid15369681">Template:Cite journal</ref><ref name="pmid26748744">Template:Cite journal</ref>
TXA2 Thromboxane receptor α and β blood platelet aggregation; blood clotting; allergic reactions NSAIDs inhibit its production to reduce incidence of strokes and heart attacks<ref name="pmid25541289" /><ref name="pmid26621246">Template:Cite journal</ref>
PGI2 Prostacyclin receptor platelet aggregation, vascular smooth muscle contraction PGI2 analogs used to treat vascular disorders like pulmonary hypertension, Raynaud's syndrome, and Buerger's disease<ref name="pmid27465880">Template:Cite journal</ref><ref name="pmid26748508">Template:Cite journal</ref><ref>Template:Cite journal</ref>
15-d-Δ12,14-PGJ2 PPARγ, Prostaglandin DP2 receptor inhibits inflammation and cell growth inhibits diverse inflammatory responses in animal models; structural model for developing anti-inflammatory agents<ref name="pmid11301410" /><ref name="pmid15369681" /><ref name="pmid26748744" />
20-HETE ? vasoconstriction, inhibits platelets inactivating mutations in the 20-HETE-forming enzyme, CYP2U1, associated with hereditary spastic paraplegia<ref name="pmid24337409">Template:Cite journal</ref>
5-Oxo-ETE OXER1 chemotactic factor for and activator of eosinophils studies needed to determine if inhibiting its production or action inhibits allergic reactions<ref name="pmid25449650" />
LTB4 LTB4R, LTB4R2 chemotactic factor for and activator of leukocytes; inflammation studies to date shown no clear benefits of LTB4 receptor antagonists for human inflammatory diseases<ref name="pmid25572555">Template:Cite journal</ref><ref name="pmid21771892">Template:Cite journal</ref><ref name="pmid24588652">Template:Cite journal</ref>
LTC4 CYSLTR1, CYSLTR2, GPR17 vascular permeability; vascular smooth muscle contraction; allergy antagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions<ref name="pmid26385352">Template:Cite journal</ref><ref name="pmid20886028">Template:Cite journal</ref>
LTD4 CYSLTR1, CYSLTR2, GPR17 vascular permeability; vascular smooth muscle contraction; allergy antagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions<ref name="pmid25572555" />
LTE4 GPR99 increases vascular permeability and airway mucin secretion thought to contribute to asthma as well as other allergic and allergic-like reactions<ref name="pmid23504326">Template:Cite journal</ref>
LxA4 FPR2 inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors<ref name="pmid25895638">Template:Cite journal</ref><ref name="pmid16968948">Template:Cite journal</ref>
LxB4 FPR2, GPR32, AHR inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors<ref name="pmid25895638" /><ref name="pmid16968948" />
RvE1 CMKLR1, inhibits BLT, TRPV1, TRPV3, NMDAR, TNFR inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors; also suppresses pain perception<ref name="pmid25052386">Template:Cite journal</ref><ref name="pmid26339646">Template:Cite journal</ref><ref name="pmid25359497">Template:Cite journal</ref>
RvE2 CMKLR1, receptor antagonist of BLT inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors<ref name="pmid25895638" /><ref name="pmid16968948" /><ref name="pmid25359497" /><ref name="pmid23747022">Template:Cite journal</ref>
14,15-EET ? vasodilation, inhibits platelets and pro-inflammatory cells role(s) in human disease not yet proven<ref name="pmid25655310">Template:Cite journal</ref><ref>Template:ClinicalTrialsGov</ref>

Prostanoids

Template:Main article Many of the prostanoids are known to mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain, and fever. Inhibition of COX-1 and/or the inducible COX-2 isoforms is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. Prostanoids also activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, and directly influence gene transcription.<ref name="Bos">Template:Cite journal</ref> Prostanoids have numerous other relevancies to clinical medicine as evidence by their use, the use of their more stable pharmacological analogs, of the use of their receptor antagonists as indicated in the following chart.

Medicine Type Medical condition or use Medicine Type Medical condition or use
Alprostadil PGE1 Erectile dysfunction, maintaining a patent ductus arteriosus in the fetus Beraprost PGI2 analog Pulmonary hypertension, avoiding reperfusion injury
Bimatoprost PGF2α analog Glaucoma, ocular hypertension Carboprost PGF2α analog Labor induction, abortifacient in early pregnancy
Dinoprostone PGE2 Labor induction Iloprost PGI2 analog Pulmonary artery hypertension
Latanoprost PGF2α analog Glaucoma, ocular hypertension Misoprostol PGE1 analog Stomach ulcers labor induction, abortifacient
Travoprost PGF2α analog Glaucoma, ocular hypertension U46619 Longer lived TX analog Research only

Cyclopentenone prostaglandins

Template:Main article PGA1, PGA2, PGJ2, Δ12-PGJ2, and 15-deox-Δ12,14-PGJ2 exhibit a wide range of anti-inflammatory and inflammation-resolving actions in diverse animal models.<ref name="pmid21843512" /> They therefore appear to function in a manner similar to specialized pro-resolving mediators although one of their mechanisms of action, forming covalent bonds with key signaling proteins, differs from those of the specialized pro-resolving mediators.

HETEs and oxo-ETEs

Template:Main article As indicated in their individual Wikipedia pages, 5-hydroxyeicosatetraenoic acid (which, like 5-oxo-eicosatetraenoic acid, acts through the OXER1 receptor), 5-oxo-eicosatetraenoic acid, 12-hydroxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, and 20-hydroxyeicosatetraenoic acid show numerous activities in animal and human cells as well as in animal models that are related to, for example, inflammation, allergic reactions, cancer cell growth, blood flow to tissues, and/or blood pressure. However, their function and relevancy to human physiology and pathology have not as yet been shown.

Leukotrienes

Template:Main article The three cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are potent bronchoconstrictors, increasers of vascular permeability in postcapillary venules, and stimulators of mucus secretion that are released from the lung tissue of asthmatic subjects exposed to specific allergens. They play a pathophysiological role in diverse types of immediate hypersensitivity reactions.<ref name="Samuelsson83">Template:Cite journal</ref> Drugs that block their activation of the CYSLTR1 receptor viz., montelukast, zafirlukast, and pranlukast, are used clinically as maintenance treatment for allergen-induced asthma and rhinitis; nonsteroidal anti-inflammatory drug-induced asthma and rhinitis (see aspirin-exacerbated respiratory disease); exercise- and cold-air induced asthma (see Exercise-induced bronchoconstriction); and childhood sleep apnea due to adenotonsillar hypertrophy (see Template:Slink).<ref name="pmid21936577">Template:Cite journalTemplate:Dead link</ref><ref name="pmid24313690">Template:Cite journal</ref><ref name="pmid26980339">Template:Cite journal</ref><ref name="pmid26678823">Template:Cite journal</ref> When combined with antihistamine drug therapy, they also appear useful for treating urticarial diseases such as hives.<ref name="pmid25515967">Template:Cite journal</ref>

Lipoxins and epi-lipoxins

Template:Main article LxA4, LxB4, 15-epi-LxA4, and 15-epi-LXB4, like other members of the specialized pro-resolving mediators class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. In a randomized controlled trial, AT-LXA4 and a comparatively stable analog of LXB4, 15R/S-methyl-LXB4, reduced the severity of eczema in a study of 60 infants<ref name="pmid22834636">Template:Cite journal</ref> and, in another study, inhaled LXA4 decreased LTC4-initiated bronchoprovocation in patients with asthma.<ref name="pmid26688348">Template:Cite journal</ref>

Eoxins

Template:Main article The eoxins (EXC4, EXD4, EXE5) are newly described. They stimulate vascular permeability in an ex vivo human vascular endothelial model system,<ref name="Primary eosinophils and mast cells">Template:Cite journal</ref> and in a small study of 32 volunteers EXC4 production by eosinophils isolated from severe and aspirin-intolerant asthmatics was greater than that from healthy volunteers and mild asthmatic patients; these findings have been suggested to indicate that the eoxins have pro-inflammatory actions and therefore potentially involved in various allergic reactions.<ref name="pmid23921438">Template:Cite journal</ref> Production of eoxins by Reed–Sternberg cells cells has also led to suggestion that they are involved in Hodgkins disease.<ref name="pmid19130894">Template:Cite journal</ref> However, the clinical significance of eoxins has not yet been demonstrated.

Resolvin metabolites of eicosapentaenoic acid

Template:Main article RvE1, 18S-RvE1, RvE2, and RvE3, like other members of the specialized pro-resolving mediators) class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. A synthetic analog of RvE1 is in clinical phase III testing (see Phases of clinical research) for the treatment of the inflammation-based dry eye syndrome; along with this study, other clinical trials (NCT01639846, NCT01675570, NCT00799552 and NCT02329743) using an RvE1 analogue to treat various ocular conditions are underway.<ref name="pmid26688348" /> RvE1 is also in clinical development studies for the treatment of neurodegenerative diseases and hearing loss.<ref name="pmid25857211">Template:Cite journal</ref>

Other metabolites of eicosapentaenoic acid

The metabolites of eicosapentaenoic acid that are analogs of their arachidonic acid-derived prostanoid, HETE, and LT counterparts include: the 3-series prostanoids (e.g. PGE3, PGD3, PGF3α, PGI3, and TXA3), the hydroxyeicosapentaenoic acids (e.g. 5-HEPE, 12-HEPE, 15-HEPE, and 20-HEPE), and the 5-series LTs (e.g. LTB5, LTC5, LTD5, and LTE5). Many of the 3-series prostanoids, the hydroxyeicosapentaenoic acids, and the 5-series LT have been shown or thought to be weaker stimulators of their target cells and tissues than their arachidonic acid-derived analogs. They are proposed to reduce the actions of their arachidonate-derived analogs by replacing their production with weaker analogs.<ref name="pmid25263947">Template:Cite journal</ref><ref name="pmid25008763">Template:Cite journal</ref> Eicosapentaenoic acid-derived counterparts of the eoxins have not been described.

Epoxyeicosanoids

Template:Main article The epoxy eicosatrienoic acids (or EETs)—and, presumably, the epoxy eicosatetraenoic acids—have vasodilating actions on heart, kidney, and other blood vessels as well as on the kidney's reabsorption of sodium and water, and act to reduce blood pressure and ischemic and other injuries to the heart, brain, and other tissues; they may also act to reduce inflammation, promote the growth and metastasis of certain tumors, promote the growth of new blood vessels, in the central nervous system, regulate the release of neuropeptide hormones, and in the peripheral nervous system inhibit or reduce pain perception.<ref name="ReferenceA" /><ref name="Apr 2014" /><ref name="Pharmacol Ther 2014" />

The ω−3 and ω−6 series

Template:Main article Template:Cquote Arachidonic acid (AA; 20:4 ω−6) sits at the head of the "arachidonic acid cascade" – more than twenty eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity, and the central nervous system.<ref name=Piomelli/>

In the inflammatory response, two other groups of dietary fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω−3) provides the most important competing cascade. DGLA (20:3 ω−6) provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory fatty acids, especially the ω−3s, has been linked to several inflammation-related diseases, and perhaps some mental illnesses.

The U.S. National Institutes of Health and the National Library of Medicine state that there is 'A' level evidence that increased dietary ω−3 improves outcomes in hypertriglyceridemia, secondary cardiovascular disease prevention, and hypertension. There is 'B' level evidence ('good scientific evidence') for increased dietary ω−3 in primary prevention of cardiovascular disease, rheumatoid arthritis, and protection from ciclosporin toxicity in organ transplant patients. They also note more preliminary evidence showing that dietary ω−3 can ease symptoms in several psychiatric disorders.<ref name="National">Template:Cite web</ref>

Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter membrane composition and function, including the composition of lipid rafts; (b) change cytokine biosynthesis; and (c) directly activate gene transcription.<ref name="Fritsche">Template:Cite journal</ref> Of these, the action on eicosanoids is the best explored

Recent data in 2024 has emerged that neuronal integrity breakdown was reduced by ω−3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group suggested fish oil supplements might help older adults fight Alzheimer's disease.<ref>Template:Cite web</ref><ref>Template:Cite journal</ref> Template:Clear

Mechanisms of ω−3 action

File:EFA to Eicosanoids.svg
EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At each step, the ω−3 and ω−6 cascades compete for the enzymes.

In general, the eicosanoids derived from AA promote inflammation, and those from EPA and from GLA (via DGLA) are less inflammatory, or inactive, or even anti-inflammatory and pro-resolving.

The figure shows the ω−3 and −6 synthesis chains, along with the major eicosanoids from AA, EPA, and DGLA.

Dietary ω−3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways, along the eicosanoid pathways:

  • Displacement—Dietary ω−3 decreases tissue concentrations of AA, so there is less to form ω−6 eicosanoids.
  • Competitive inhibition—DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosanoids.
  • Counteraction—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts.

Role in inflammation

Since antiquity, the cardinal signs of inflammation have been known as: calor (warmth), dolor (pain), tumor (swelling), and rubor (redness). The eicosanoids are involved with each of these signs.

Redness—An insect's sting will trigger the classic inflammatory response. Short acting vasoconstrictors — TXA2 — are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the vasodilators PGE2 and LTB4. The blood vessels engorge and the injury reddens.
Swelling—LTB4 makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also loses pro-inflammatory cytokines.
Pain—The cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons.
Heat—PGE2 is also a potent pyretic agent. Aspirin and NSAIDS—drugs that block the COX pathways and stop prostanoid synthesis—limit fever or the heat of localized inflammation.

History

In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized prostaglandin as a component of semen. Between 1929 and 1932, George and Mildred Burr showed that restricting fat from animals' diets led to a deficiency disease, and first described the essential fatty acids.<ref name="Burr">Template:Cite journal</ref> In 1935, von Euler identified prostaglandin. In 1964, Bergström and Samuelsson linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids.<ref name="Bergström">Template:Cite journal</ref> In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.<ref name="Vane">Template:Cite journal</ref> Von Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and Bergström also received in 1982. E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.

See also

References

Template:Reflist

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