Eicosanoid


Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids 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.
There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and eoxins. 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. 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. 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

Fatty acid sources

"Eicosanoid" is the collective term for straight-chain PUFAs 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, i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid is an ω−6 fatty acid with four double bonds in the cis configuration, each located between carbons 5-6, 8-9, 11-12, and 14-15.
  • Adrenic acid, 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, 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, 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,
  • one A-B-C sequence-letter,
  • 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 while leukotrienes derived from EPA have five double bonds.
  • *The AA-derived prostanoids have two double bonds while their AA-derived leukotrienes have four double bonds.
  • Hydroperoxy-, hydroxyl-, and oxo-eicosanoids possess a hydroperoxy, hydroxy, or oxygen atom 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 ; H for a hydroxy residue ; and oxo- for an oxo residue. The number of their double bonds is indicated by their full and trivial names: AA-derived hydroxy metabolites have four double bonds double bonds ; and DGLA-derived hydroxy metabolites have three double bonds.
The stereochemistry of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters. For hydroperoxy and hydroxy eicosanoids an S or R designates the chirality of their substituents -, 5S-hydroxy-, and 5-hydroxy-eicosatetraenoic acid] is given the trivial names of 5S-HETE, 5-HETE, 5S-HETE, or 5. 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. Nonetheless, certain eicosanoid-forming pathways do form R isomers and their S'' versus R isomeric products can exhibit dramatically different biological activities. 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:
  • ω−6 series eicosanoids derived from arachidonic acid:
  • *Hydroxyeicosatetraenoic acids include the following metabolites of arachidonic acid:
  • **5-HETE, 12-HETE, 15-hydroxyeicosatetraenoic acid, 20-hydroxyeicosatetraenoic acid, and 19-HETE.
  • *Leukotrienes include the following metabolites of arachidonic acid:
  • **LTA4, LTB44, LTC4, LTD4, and LTE4.
  • *Eoxins include the following metabolites of arachidonic acid:
  • **EXA4, EXC4, EXD4, and EXE4.
  • *Prostanoids consisting of several different types:
  • **Prostaglandins include the following metabolites of arachidonic acid:
  • ***PGG2, PGH2, PGE2, PGD2, PGF2α, PGA2, PGB2.
  • **Prostacyclins include:
  • ***PGI2.
  • **Thromboxanes include the following metabolites of arachidonic acid:
  • ***TXA2 and TXB2.
  • **Cyclopentenone prostaglandins include the following metabolites of arachidonic acid:
  • ***PGA1, PGA2.
  • ω−6 series eicosanoids derived from dihomo-gamma-linolenic acid. These metabolites are analogs of arachidonic acid-derived eicosanoids but lack a double bond between carbons 5 and 6 and therefore have 1 less double bond than their arachidonic acid-derived analogs. They are the following:
  • *PGA1, PGE1, and TXA1.
  • ω−3 series eicosanoids:
  • *Resolvins of the E series . RvE include the following metabolites of eicosapentaenoic acid:
  • **RvE1, 18S-RvE1, RvE2, and RvE3.
  • *Other ω−3 series eicosapentaenoic acid-derived eicosanoids are analogs of ω−6 fatty acid-derived metabolites but contain a double bond between carbon 17 and 18 and therefore have one more double bond than their arachidonic acid-derived analogs. They include :
  • **5-HEPE, 12-HEPE, 15-HEPE, and 20-HETE; LTA5, LTB5, LTC5, LTD5, and LTE5 ; PGE3, PGD3, PGF3α, and Δ-6-keto PGF1α; PGI3 ; and TXA3 and TXB3.
  • ω−9 series eicosanoids
  • *Hydroxy are derived form mead acid, is metabolized to the 3 double bond-containing analog of 5-HETE viz., 5-HETrE.

Hydroxyeicosatetraenoic acids, leukotrienes, eoxins and prostanoids are sometimes termed "classic eicosanoids".

Nonclassic eicosanoids

In contrast to the classic eicosanoids, several other classes of PUFA metabolites have been termed 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'. These included the following classes:
  • Oxoeicosanoids include the following metabolites:
  • *5-Oxo-eicosatetraenoic acid, 12-oxo-ETE, and 15-oxo-ETE, which are metabolites of arachidonic acid and 5-oxo-ETrE which is a metabolite of mead acid.
  • Hepoxilins include the following arachidonic acid metabolites:
  • * HxA3 and HxB3.
  • Lipoxins include the following metabolites of arachidonic acid:
  • * LxA4 and LxB4.
  • Epi-lipoxins include the following metabolites of arachidonic acid:
  • * 15-epi-LxA4 and 15-epi-LxB4.
  • Epoxyeicosatrienoic acids include the following metabolites of arachidonic acid:
  • *5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET.
  • Epoxyeicosatetraenoic acids include the following metabolites of eicosapentaenoic acid:
  • *5,6-EEQ, 8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 15,16-EEQ.
  • Isoprostanes are non-enzymatically formed derivatives of polyunsaturated fatty acids studied as markers of oxidative stress; they include the following arachidonic acid-derived isoPs which are named based on their structural similarities to PGs:
  • *D2-isoPs, E2-isoPs, A2-isoPs, and J2-isoPs; and two epoxide-containing isoPs, 5,6-epoxyisoprostane E2 and 5,6-epoxyisoprostane A2. Some of these isoPs have been shown to possess anti-inflammatory activity.
  • Isofurans are non-enzymatically formed derivatives of polyunsaturated fatty acids that possess a furan ring structure; they are studied as markers of oxidative stress. There are 256 potentially different furan ring-containing isomers that can be derived from arachidonic acid.
  • Endocannabinoids are certain glycerolipids or dopamine that are esterified to polyunsaturated fatty acids that activate cannabinoid receptors. They include the following arachidonic acid-esterified agents:
  • *Arachidonoylethanolamine, 2-arachidonoylglycerol, 2-arachidonyl glyceryl ether, O-arachidonoyl-ethanolamine, and N-arachidonoyl dopamine.
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-hydroxy-6E,8Z,11Z-eicosatrienoic acid, 5-oxo-6,8,11-eicosatrienoic acid, LTA3, and LTC3 involve the same enzymatic pathways that make their arachidonic acid-derived analogs.