View source for Eicosanoid

{{Short description|Class of compounds}}
[[File:Eicosanoid synthesis.svg|right|thumb|400px|Pathways in biosynthesis of '''eicosanoid'''s from arachidonic acid: there are parallel paths from [[Eicosapentaenoic acid|EPA]] & [[Dihomo-gamma-linolenic acid|DGLA]].]]

'''Eicosanoids''' are [[lipid signaling|signaling molecules]] made by the [[enzymatic]] or non-enzymatic [[oxidation]] of [[arachidonic acid]] or other [[polyunsaturated fatty acid]]s (PUFAs) that are, similar to [[arachidonic acid]], around 20 carbon units in length. Eicosanoids are a sub-category of [[oxylipin]]s, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as [[cell signal]]ing molecules. Eicosanoids function in diverse [[physiological system]]s and pathological processes such as: mounting or inhibiting [[inflammation]], [[allergy]], [[fever]] and other [[immune response]]s; 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 [[prostaglandin]]s, may also have [[endocrine]] roles as [[hormone]]s to influence the function of distant cells.<ref name="tmbp">{{Cite web|url=https://themedicalbiochemistrypage.org/eicosanoids.php|title=Eicosanoid Synthesis and Metabolism: Prostaglandins, Thromboxanes, Leukotrienes, Lipoxins |publisher=The Medical Biochemistry Page|date=2024|access-date=9 April 2024}}</ref><ref>{{Cite web |date=2018-07-21 |title=15.2C: Chemistry of Hormones |url=https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Anatomy_and_Physiology_(Boundless)/15%3A_Endocrine_System/15.2%3A_Hormones/15.2C%3A_Chemistry_of_Hormones |access-date=2024-04-09 |website=Medicine LibreTexts |language=en}}</ref>

There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins, [[thromboxane]]s, [[leukotriene]]s, [[lipoxin]]s, [[resolvin]]s, and [[eoxin]]s.<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">{{Cite journal |vauthors=Edwards IJ, O'Flaherty JT |year=2008 |title=Omega-3 Fatty Acids and PPARgamma in Cancer |journal=PPAR Research |volume=2008 |article-number=358052 |doi=10.1155/2008/358052 |pmc=2526161 |pmid=18769551 |doi-access=free}}</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">{{Cite journal |last1=DeCaterina, R |last2=Basta, G |date=June 2001 |title=n-3 Fatty acids and the inflammatory response – biological background |journal=European Heart Journal Supplements |volume=3, Suppl D |pages=D42–D49 |doi=10.1016/S1520-765X(01)90118-X|s2cid=22691568 |doi-access=free }}</ref><ref name="Funk">{{Cite journal |last=Funk, Colin D. |date=30 November 2001 |title=Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology |journal=Science |volume=294 |issue=5548 |pages=1871–1875 |bibcode=2001Sci...294.1871F |doi=10.1126/science.294.5548.1871 |pmid=11729303}}</ref><ref name="Piomelli">{{Cite journal |last=Piomelli, Daniele |year=2000 |title=Arachidonic Acid |url=http://www.acnp.org/g4/GN401000059/Default.htm |journal=Neuropsychopharmacology: The Fifth Generation of Progress |archive-url=https://web.archive.org/web/20060715122827/http://www.acnp.org/g4/GN401000059/Default.htm |archive-date=2006-07-15 |access-date=2006-03-03}}</ref><ref name="Soberman">{{Cite journal |last1=Soberman, Roy J. |last2=Christmas, Peter |year=2003 |title=The organization and consequences of eicosanoid signaling |journal=J. Clin. Invest. |volume=111 |issue=8 |pages=1107–1113 |doi=10.1172/JCI18338 |pmc=152944 |pmid=12697726}}</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==
{{see also|Essential fatty acid interactions#Eicosanoid series nomenclature}}

===Fatty acid sources===
"Eicosanoid"  ({{ety|el|[[wikt:eicosa-|eicosa-]]|twenty}}) is the collective term<ref name="Beare">{{Cite web |last=Beare-Rogers |year=2001 |title=IUPAC Lexicon of Lipid Nutrition |url=http://www.iupac.org/publications/pac/2001/pdf/7304x0685.pdf |access-date=June 1, 2006}}</ref> for [[straight-chain]] PUFAs ([[polyunsaturated fatty acid]]s) 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. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid is an [[omega-6 fatty acid|ω−6 fatty acid]] with four [[double bond]]s in the [[Cis–trans isomerism|''cis'' configuration]] (denoted ''Z'' in [[E–Z notation]]), each located between carbons 5-6, 8-9, 11-12, and 14-15 (see [[IUPAC nomenclature of organic chemistry#Basic principles|carbon numbering]]).
* [[Adrenic acid]] ('''AdA'''), i.e. 7''Z'',10''Z'',13''Z'',16''Z''-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. 5''Z'',8''Z'',11''Z'',14''Z'',17''Z''-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. 8''Z'',11''Z'',14''Z''-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. 5''Z'',8''Z'',11''Z''-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 group]]s 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 {{Cite web |last=Cyberlipid Center |title=Prostanoids |url=http://www.cyberlipid.org/prost1/pros0001.htm |archive-url=https://web.archive.org/web/20070208145938/http://www.cyberlipid.org/prost1/pros0001.htm |archive-date=2007-02-08 |access-date=2007-02-05}}</ref>
*A subscript or plain script number following the designated eicosanoid's trivial name indicates the number of its [[Covalent bond|double bonds]]. Examples are:
** The EPA-derived prostanoids have three double bonds (e.g. PGG<sub>3</sub> or PGG3) while leukotrienes derived from EPA have five double bonds (e.g. LTB<sub>5</sub> or LTB5).
**The AA-derived prostanoids have two double bonds (e.g. PGG<sub>2</sub> or PGG2) while their AA-derived leukotrienes have four double bonds (e.g. LTB<sub>4</sub> 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-<u>Hp</u>ETE or 5-<u>HP</u>ETE); H for a hydroxy residue (e.g. 5-hydroxy-eicosatetraenoic acid or 5-<u>H</u>ETE); and oxo- for an oxo residue (e.g. 5-oxo-eicosatetraenioic acid or 5-<u>oxo</u>-ETE or 5-<u>oxo</u>ETE). 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-eicosa<u>tetra</u>enoic acid or 5-HE<u>T</u>E; EPA-derived hydroxy metabolites have five ('penta' or 'P') double bonds (e.g. 5-hydroxy-eicosa<u>penta</u>enoic acid or 5-HE<u>P</u>E); and DGLA-derived hydroxy metabolites have three ('tri' or 'Tr') double bonds (e.g. 5-hydroxy-eicosa<u>tri</u>enoic acid or 5-HE<u>Tr</u>E).

The [[stereochemistry]] of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters (e.g. PGF<sub>2α</sub> versus PGF<sub>2β</sub>). For hydroperoxy and hydroxy eicosanoids an ''S'' or ''R'' designates the [[chirality]] of their substituents (e.g. 5''S''-hydroxy-eicosateteraenoic acid [also termed 5(''S'')-, 5S-hydroxy-, and 5(S)-hydroxy-eicosatetraenoic acid] is given the trivial names of 5''S''-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. 5''S''-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">{{Cite journal |vauthors=Rossi AG, Thomas MJ, O'Flaherty JT |year=1988 |title=Stereospecific actions of 5-hydroxyeicosatetraenoate |journal=FEBS Letters |volume=240 |issue=1–2 |pages=163–166 |doi=10.1016/0014-5793(88)80360-0 |pmid=3191990 |doi-access=free |s2cid=43027447}}</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:
*ω−6 series eicosanoids derived from arachidonic acid:
**[[Hydroxyeicosatetraenoic acid]]s ('''HETE''') include the following metabolites of arachidonic acid:
***[[5-HETE]], [[12-HETE]], [[15-hydroxyeicosatetraenoic acid]] (i.e. 15-HETE), [[20-hydroxyeicosatetraenoic acid]] (i.e. 20-HETE), and 19-HETE.
**[[Leukotriene]]s ('''LT''') include the following metabolites of arachidonic acid:
***[[LTA4|LTA<sub>4</sub>]], [[LTB4|LTB4<sub>4</sub>]], [[LTC4|LTC<sub>4</sub>]], [[LTD4|LTD<sub>4</sub>]], and [[LTE4|LTE<sub>4</sub>]].
**[[Eoxin]]s ('''EX''') include the following metabolites of arachidonic acid:
***[[EXA4|EXA<sub>4</sub>]], [[EXC4|EXC<sub>4</sub>]], [[EXD4|EXD<sub>4</sub>]], and [[EXE4|EXE<sub>4</sub>]].
**[[Prostanoid]]s consisting of several different types: 
***[[Prostaglandin]]s ('''PG''') include the following metabolites of arachidonic acid:
****[[PGG2|PGG<sub>2</sub>]], [[PGH2|PGH<sub>2</sub>]], [[PGE2|PGE<sub>2</sub>]], [[PGD2|PGD<sub>2</sub>]], [[PGF2alpha|PGF<sub>2α</sub>]], PGA<sub>2</sub>, PGB<sub>2</sub> (see {{slink|Specialized pro-resolving mediators|Prostaglandins and isoprostanes}}).
***[[Prostacyclin]]s include:
****[[PGI2|PGI<sub>2</sub>]].
***[[Thromboxane]]s ('''TX''') include the following metabolites of arachidonic acid:
****[[TXA2|TXA<sub>2</sub>]] and [[TXB2|TXB<sub>2</sub>]].
***[[Cyclopentenone prostaglandin]]s include the following metabolites of arachidonic acid:
****PGA<sub>1</sub>, PGA<sub>2</sub> (see [[Prostanoid]], PGJ<sub>2</sub>, Δ12-PGJ<sub>2</sub>, and 15-deoxy-Δ12,14-PGJ<sub>2</sub>).<ref name="pmid11301410">{{Cite journal |vauthors=Straus DS, Glass CK |year=2001 |title=Cyclopentenone prostaglandins: new insights on biological activities and cellular targets |journal=Medicinal Research Reviews |volume=21 |issue=3 |pages=185–210 |doi=10.1002/med.1006.abs |pmid=11301410}}</ref>  
*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:
**PGA<sub>1</sub>, PGE<sub>1</sub>, and TXA<sub>1</sub>.<ref name="pmid10682224">{{Cite journal |vauthors=Prasad KN, Hovland AR, Cole WC, Prasad KC, Nahreini P, Edwards-Prasad J, Andreatta CP |year=2000 |title=Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale |journal=Clinical Neuropharmacology |volume=23 |issue=1 |pages=2–13 |doi=10.1097/00002826-200001000-00002 |pmid=10682224}}</ref><ref name="pmid24923568">{{Cite journal |vauthors=Xu Y, Qian SY |year=2014 |title=Anti-cancer activities of ω-6 polyunsaturated fatty acids |journal=Biomedical Journal |volume=37 |issue=3 |pages=112–119 |doi=10.4103/2319-4170.131378 |pmc=4166599 |pmid=24923568 |doi-access=free }}</ref>
*ω−3 series eicosanoids:
**[[Resolvin]]s of the E series ('''RvE''') (D series resolvins [RvD] are metabolites of the 22-carbon ω−3 fatty acid [[docosahexaenoic acid]]; see {{slink|Specialized pro-resolving mediators|DHA-derived resolvins}}). 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 (HEPE is hydroxyeicosapentaenoic acid):
***5-HEPE, 12-HEPE,<ref name="pmid21236358">{{Cite journal |vauthors=Gomolka B, Siegert E, Blossey K, Schunck WH, Rothe M, Weylandt KH |year=2011 |title=Analysis of omega-3 and omega-6 fatty acid-derived lipid metabolite formation in human and mouse blood samples |journal=Prostaglandins & Other Lipid Mediators |volume=94 |issue=3–4 |pages=81–87 |doi=10.1016/j.prostaglandins.2010.12.006 |pmid=21236358}}</ref> 15-HEPE,<ref name="pmid17540633">{{Cite journal |vauthors=Zulfakar MH, Edwards M, Heard CM |year=2007 |title=Is there a role for topically delivered eicosapentaenoic acid in the treatment of psoriasis? |url=https://www.jle.com/10.1684/ejd.2007.0201 |journal=European Journal of Dermatology |volume=17 |issue=4 |pages=284–291 |doi=10.1684/ejd.2007.0201 |doi-broken-date=12 July 2025 |pmid=17540633}}</ref> and 20-HETE;<ref name="pmid22730630">{{Cite journal |vauthors=Caramia G |year=2012 |title=[Essential fatty acids and lipid mediators. Endocannabinoids] |journal=La Pediatria Medica e Chirurgica: Medical and Surgical Pediatrics |language=it |volume=34 |issue=2 |pages=65–72 |doi=10.4081/pmc.2012.2 |pmid=22730630 |doi-access=free}}</ref> LTA5, LTB5, LTC5, LTD5, and LTE5 (see {{slink|Arachidonate 5-lipoxygenase|Eicosapentaenoic acid}});<ref name="pmid26771963">{{Cite journal |vauthors=Wiktorowska-Owczarek A, Berezińska M, Nowak JZ |year=2015 |title=PUFAs: Structures, Metabolism and Functions |journal=Advances in Clinical and Experimental Medicine |volume=24 |issue=6 |pages=931–941 |doi=10.17219/acem/31243 |pmid=26771963 |doi-access=free}}</ref> PGE<sub>3</sub>, PGD<sub>3</sub>, PGF<sub>3α</sub>, and Δ(17)-6-keto PGF<sub>1α</sub>;<ref name="pmid26771963" /><ref name="pmid24996760">{{Cite journal |vauthors=Tanaka N, Yamaguchi H, Furugen A, Ogura J, Kobayashi M, Yamada T, Mano N, Iseki K |year=2014 |title=Quantification of intracellular and extracellular eicosapentaenoic acid-derived 3-series prostanoids by liquid chromatography/electrospray ionization tandem mass spectrometry |journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids |volume=91 |issue=3 |pages=61–71 |doi=10.1016/j.plefa.2014.04.005 |pmid=24996760}}</ref> PGI<sub>3</sub> (see {{slink|Essential fatty acid interactions|Counteraction}});<ref name="pmid26771963" /> and TXA<sub>3</sub> and TXB<sub>3</sub>.<ref name="pmid26771963" />
*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 (see {{slink|Arachidonate 5-lipoxygenase|Mead acid}}).
  
Hydroxyeicosatetraenoic acids, leukotrienes, eoxins and prostanoids are sometimes termed "classic eicosanoids".<ref name="vandyke">{{Cite journal |vauthors=Van Dyke TE, Serhan CN |year=2003 |title=Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases |journal=J. Dent. Res. |volume=82 |issue=2 |pages=82–90 |doi=10.1177/154405910308200202 |pmid=12562878 |s2cid=40812937}}</ref><ref name="Serhan">{{Cite journal |vauthors=Serhan CN, Gotlinger K, Hong S, Arita M |year=2004 |title=Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis |journal=Prostaglandins Other Lipid Mediat. |volume=73 |issue=3–4 |pages=155–172 |doi=10.1016/j.prostaglandins.2004.03.005 |pmid=15290791}}</ref><ref name="Anderle">{{Cite journal |vauthors=Anderle P, Farmer P, Berger A, Roberts MA |year=2004 |title=Nutrigenomic approach to understanding the mechanisms by which dietary long-chain fatty acids induce gene signals and control mechanisms involved in carcinogenesis |journal=Nutrition (Burbank, Los Angeles County, Calif.) |volume=20 |issue=1 |pages=103–108 |doi=10.1016/j.nut.2003.09.018 |pmid=14698023}}</ref>

===Nonclassic eicosanoids===
In contrast to the classic eicosanoids, several other classes of PUFA metabolites have been termed 'novel', 'eicosanoid-like' or '[[nonclassic eicosanoid]]s'.<ref name="Evans">{{Cite journal |display-authors=etal |vauthors=Evans AR, Junger H, Southall MD |year=2000 |title=Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons |journal=J. Pharmacol. Exp. Ther. |volume=293 |issue=3 |pages=912–920 |doi=10.1016/S0022-3565(24)39314-0 |pmid=10869392}}</ref><ref name="O">{{Cite journal |vauthors=O'Brien WF, Krammer J, O'Leary TD, Mastrogiannis DS |year=1993 |title=The effect of acetaminophen on prostacyclin production in pregnant women |journal=Am. J. Obstet. Gynecol. |volume=168 |issue=4 |pages=1164–1169 |doi=10.1016/0002-9378(93)90362-m |pmid=8475962}}</ref><ref name="pmid11306946">{{Cite journal |vauthors=Behrendt H, Kasche A, Ebner von Eschenbach C, Risse U, Huss-Marp J, Ring J |year=2001 |title=Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization |url=http://mediatum.ub.tum.de/doc/1218757/document.pdf |journal=Int. Arch. Allergy Immunol. |volume=124 |issue=1–3 |pages=121–125 |doi=10.1159/000053688 |pmid=11306946 |s2cid=53331}}</ref><ref name="pmid10477044">{{Cite journal |display-authors=etal |vauthors=Sarau HM, Foley JJ, Schmidt DB |year=1999 |title=In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity |journal=Prostaglandins Leukot. Essent. Fatty Acids |volume=61 |issue=1 |pages=55–64 |doi=10.1054/plef.1999.0074 |pmid=10477044}}</ref> These included the following classes:
*[[Oxoeicosanoid]]s ('''oxo-ETE''') include the following metabolites:
**[[5-Oxo-eicosatetraenoic acid]] (5-oxo-ETE), 12-oxo-ETE (see {{slink|12-HETE|Further metabolism}}), and 15-oxo-ETE, which are metabolites of arachidonic acid (see [[15-Hydroxyeicosatetraenoic acid]]) and 5-oxo-ETrE which is a metabolite of mead acid (see {{slink|Arachidonate 5-lipoxygenase|Mead acid}}).
*[[Hepoxilin]]s ('''Hx''') include the following arachidonic acid metabolites:
** HxA<sub>3</sub> and HxB<sub>3</sub>.
*[[Lipoxin]]s ('''Lx''') include the following metabolites of arachidonic acid:
** LxA<sub>4</sub> and LxB<sub>4</sub> (see [[Specialized pro-resolving mediators]]).  
*[[Epi-lipoxin]]s ('''epi-Lx''') include the following metabolites of arachidonic acid:
** 15-epi-LxA<sub>4</sub> (also termed AT-LxA<sub>4</sub>) and 15-epi-LxB<sub>4</sub> (also termed AT-LxB<sub>4</sub>).
*[[Epoxyeicosatrienoic acid]]s ('''EET''') include the following metabolites of arachidonic acid:
**5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET.
*[[Epoxyeicosatetraenoic acid]]s ('''EEQ''') include the following metabolites of eicosapentaenoic acid:
**5,6-EEQ, 8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 15,16-EEQ.
*[[Isoprostane]]s ('''isoP''') are non-enzymatically formed derivatives of [[polyunsaturated fatty acid]]s studied as markers of [[oxidative stress]]; they include the following arachidonic acid-derived isoPs which are named based on their structural similarities to PGs:<ref name="pmid26670350">{{Cite journal |vauthors=Czerska M, Zieliński M, Gromadzińska J |year=2016 |title=Isoprostanes - A novel major group of oxidative stress markers |journal=International Journal of Occupational Medicine and Environmental Health |volume=29 |issue=2 |pages=179–190 |doi=10.13075/ijomeh.1896.00596 |pmid=26670350 |doi-access=free}}</ref><ref name="pmid27422370">{{Cite journal |vauthors=Friedli O, Freigang S |year=2016 |title=Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1862 |issue=4 |pages=382–392 |doi=10.1016/j.bbalip.2016.07.006 |pmid=27422370 |doi-access=free}}</ref>
**D<sub>2</sub>-isoPs, E<sub>2</sub>-isoPs, A<sub>2</sub>-isoPs, and J<sub>2</sub>-isoPs; and two epoxide-containing isoPs, 5,6-epoxyisoprostane E<sub>2</sub> and 5,6-epoxyisoprostane A<sub>2</sub>. Some of these isoPs have been shown to possess anti-inflammatory activity (see {{slink|Specialized pro-resolving mediators|Prostaglandins and isoprostanes}}). 
*[[Isofuran]]s 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.<ref name="pmid27519299">{{Cite journal |vauthors=Cuyamendous C, de la Torre A, Lee YY, Leung KS, Guy A, Bultel-Poncé V, Galano JM, Lee JC, Oger C, Durand T |year=2016 |title=The novelty of phytofurans, isofurans, dihomo-isofurans and neurofurans: Discovery, synthesis and potential application |url=https://hal.archives-ouvertes.fr/hal-02593271/file/Cuyamendous%20Biochimie%202016%2C%2049-62_HAL.pdf |journal=Biochimie |volume=130 |pages=49–62 |doi=10.1016/j.biochi.2016.08.002 |pmid=27519299 |s2cid=1504539}}</ref>
*[[Cannabinoid#Endogenous cannabinoids|Endocannabinoids]] are certain [[glycerolipid]]s or dopamine that are esterified to polyunsaturated fatty acids that activate [[cannabinoid receptor]]s. They include the following arachidonic acid-esterified agents:
**[[Arachidonoylethanolamine]], [[2-arachidonoylglycerol]], [[2-arachidonyl glyceryl ether]], [[O-arachidonoyl-ethanolamine|''O''-arachidonoyl-ethanolamine]], and [[N-arachidonoyl dopamine|''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(S)-hydroxy-6E,8Z,11Z-eicosatrienoic acid (5-HETrE), 5-oxo-6,8,11-eicosatrienoic acid (5-oxo-ETrE), LTA<sub>3</sub>, and LTC<sub>3</sub> involve the same enzymatic pathways that make their arachidonic acid-derived analogs.

==Biosynthesis==
Eicosanoids typically are not stored within cells but rather [[Biosynthesis|synthesized]] as required. They derive from the [[fatty acid]]s that make up the [[cell membrane]] and [[Nuclear envelope|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 [[pathogen]]s, or stimuli made by nearby cells, tissues, or pathogens such as [[Chemotaxis|chemotactic factor]]s, [[cytokine]]s, [[growth factor]]s, and even certain eicosanoids. The activated cells then mobilize enzymes, termed [[Phospholipase A2|phospholipases A<sub>2</sub>]] (PLA<sub>2</sub>), capable of releasing ω−6 and ω−3 fatty acids from membrane storage. These fatty acids are bound in [[ester]] linkage to the [[Phospholipase A2|SN2]] position of membrane [[phospholipid]]s; PLA<sub>2</sub> act as [[esterase]]s to release the fatty acid. There are several classes of PLA<sub>2</sub> with type IV cytosolic PLA<sub>2</sub> (cPLA<sub>2</sub>) appearing to be responsible for releasing the fatty acids under many conditions of cell activation. The cPLA<sub>2</sub> act specifically on phospholipids that contain AA, EPA or GPLA at their SN2 position. cPLA<sub>2</sub> may also release the lysophospholipid that becomes [[platelet-activating factor]].<ref name="University">{{Cite web |last=University of Kansas Medical Center |year=2004 |title=Eicosanoids and Inflammation |url=http://classes.kumc.edu/som/bioc801/small_group/eicosanoids/eicosanoids-2004.pdf |archive-url=https://web.archive.org/web/20050516013327/http://classes.kumc.edu/som/bioc801/small_group/eicosanoids/eicosanoids-2004.pdf |archive-date=2005-05-16 |access-date=2007-01-05}}</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 [[Cyclooxygenase|COX]]) add [[Oxygen|molecular oxygen]] (O<sub>2</sub>).  Although the fatty acid is [[Symmetry|symmetric]], the resulting eicosanoids are [[Chirality (chemistry)|chiral]]; the oxidations proceed with high [[stereoselectivity]] (enzymatic oxidations are considered practically [[Stereospecificity|stereospecific]]).

Four families of [[enzyme]]s initiate or contribute to the initiation of the catalysis of fatty acids to eicosanoids:
*[[Cyclooxygenase]]s (COXs): [[COX-1]] and [[COX-2]] initiate the metabolism of [[arachidonic acid]] to [[prostanoid]]s that contain two double bonds, i.e. the [[prostaglandin]]s (e.g. PGE<sub>2</sub>), [[prostacyclin]]s (i.e. PGI<sub>2</sub>), and [[thromboxane]]s (e.g. TXA<sub>2</sub>). 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. PGE<sub>3</sub>, PGI<sub>3</sub>, and TXA<sub>3</sub> 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. PGE<sub>1</sub>, PGI<sub>1</sub>, and TXA<sub>1</sub>.<ref name="pmid26374175">{{Cite journal |vauthors=Gabbs M, Leng S, Devassy JG, Monirujjaman M, Aukema HM |year=2015 |title=Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs |journal=Advances in Nutrition |volume=6 |issue=5 |pages=513–540 |doi=10.3945/an.114.007732 |pmc=4561827 |pmid=26374175}}</ref> 
*[[Lipoxygenase]]s (LOXs): [[Arachidonate 5-lipoxygenase|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 [[leukotriene]]s (e.g. LTB<sub>4</sub> and [[LTC4|LTC<sub>4</sub>]]); 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, [[eoxin]]s, 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, [[hepoxilin]]s, 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), LTB<sub>5</sub>, LTC<sub>5</sub>, 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 LTB<sub>5</sub>, 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">{{Cite journal |vauthors=Powell WS, Rokach J |year=2015 |title=Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1851 |issue=4 |pages=340–355 |doi=10.1016/j.bbalip.2014.10.008 |pmc=5710736 |pmid=25449650}}</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 5''S''-HpETE, 5''S''-HETE, 12''S''-HpETE, 12''S''-HETE, 15''S''-HpETE and, 15''S''-HETE. [[ALOX12B]] (i.e. arachidonate 12-lipoxygenase, 12R type) forms ''R'' chirality products, i.e. 12''R''-HpETE and 12''R''-HETE. Similarly, [[ALOXE3]] (i.e. epidermis-type lipoxygenase 3 or eLOX3) metabolizes arachidonic acid to 12''R''-HpETE and 12''R''-HETE; however these are minor products that this enzyme forms only under a limited set of conditions. ALOXE3 preferentially metabolizes arachidonic acid to hepoxilins.    
*[[Epoxygenase]]s: these are [[cytochrome P450]] enzymes which generate [[nonclassic eicosanoid]] [[epoxide]]s 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 [[lipoxin]]s and with [[cytochrome P450]] monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series [[resolvin]]s (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">{{Cite journal |vauthors=Capra V, Rovati GE, Mangano P, Buccellati C, Murphy RC, Sala A |year=2015 |title=Transcellular biosynthesis of eicosanoid lipid mediators |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1851 |issue=4 |pages=377–382 |doi=10.1016/j.bbalip.2014.09.002 |pmid=25218301}}</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 [[Protein isoform|isoform]]s.<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 [[peroxide]]s. LTA<sub>4</sub> can form [[adduct]]s with tissue [[DNA]]. Other reactions of lipoxygenases generate cellular damage; [[Murinae|murine]] models implicate 15-lipoxygenase in the [[pathogenesis]] of [[atherosclerosis]].<ref name="Cyrus">{{Cite journal |last1=Cyrus, Tillmann |last2=Witztum |first2=Joseph L. |last3=Rader |first3=Daniel J. |last4=Tangirala |first4=Rajendra |last5=Fazio |first5=Sergio |last6=Linton |first6=Macrae F. |last7=Funk |first7=Colin D. |date=June 1999 |title=Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice |journal=J Clin Invest |volume=103 |issue=11 |pages=1597–1604n |doi=10.1172/JCI5897 |pmc=408369 |pmid=10359569}}</ref><ref name="Schewe">{{Cite journal |last=Schewe T. |date=Mar–Apr 2002 |title=15-lipoxygenase-1: a prooxidant enzyme |journal=Biol. Chem. |volume=383 |issue=3–4 |pages=365–374 |doi=10.1515/BC.2002.041 |pmid=12033428 |s2cid=7487557}}</ref>
The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage.
The enzymes that are biosynthetic for eicosanoids (e.g., [[Glutathione S-transferase A1|glutathione-S-transferase]]s, epoxide [[hydrolase]]s, and [[carrier protein]]s) 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 [[Transcription (biology)|DNA transcription]] there;
LTB<sub>4</sub> is ligand for [[Peroxisome proliferator-activated receptor|PPARα]].<ref name=Funk/>
''(See diagram at [[Peroxisome proliferator-activated receptor|PPAR]].)''
{| width="550" style="border: 1px solid black; border-image: none;" align="center" border="0"
|+'''Structures of selected eicosanoids'''
|-
| align="center"|[[File:Prostaglandin E1.svg|200px]]
| colspan="2" align="center"| [[File:Thromboxane A2 acsv.svg|170px]]<!--18Oct07: narrowed 2nd/3rd images from 200px-->
| align="center"| [[File:Leukotriene B4.svg|180px]]
|-
| align="center" | Prostaglandin E<sub>1</sub>.  The 5-member ring is characteristic of the class.
| colspan="2" align="center"| Thromboxane A<sub>2</sub>. Oxygens<br />have moved into the ring.
| align="center"| Leukotriene B<sub>4</sub>.  Note the 3 conjugated double bonds.
|-
| colspan="2" align="center"| [[File:Prostaglandin I2.png|200px]]
| colspan="2" align="center"|[[File:Leukotriene E4.svg|200px]]
|-
| colspan="2" align="center"| Prostacyclin I<sub>2</sub>.  The second ring distinguishes it from the prostaglandins.
| colspan="2" align="center"|Leukotriene E<sub>4</sub>, an example of a cysteinyl leukotriene.
|}

=== Prostanoid pathways ===
{{see also|Prostanoid#Biosynthesis of prostaglandins}}
Both COX1 and COX2 (also termed prostaglandin-endoperoxide synthase-1 ([[PTGS1]]) and [[PTGS2]], respectively) metabolize arachidonic acid by adding molecular O<sub>2</sub> between carbons 9 and 11 to form an [[Organic peroxides|endoperoxide]] bridge between these two carbons, adding molecular O<sub>2</sub> 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 PGG<sub>2</sub>, a product that has two fewer double bonds than arachidonic acid. The 15-hydroperoxy residue of PGG<sub>2</sub> is then reduced to a 15-[[Hydroxy group|hydroxyl]] residue thereby forming PGH<sub>2</sub>. PGH<sub>2</sub> 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 [[isozyme]]s, [[PTGES]], [[PTGES2]], or [[PTGES3]], convert PGH<sub>2</sub> to PGE<sub>2</sub> (subsequent products of this pathway include PGA<sub>2</sub> and PGB<sub>2</sub> (see {{slink|Prostanoid|Biosynthesis of prostaglandins}}); '''b)''' PGF synthase which converts PGH<sub>2</sub> to PGF<sub>2α</sub>; '''c)''' [[Prostaglandin D2 synthase|Prostaglandin D<sub>2</sub> synthase]] which converts PGH<sub>2</sub> to PGD<sub>2</sub> (subsequent products in this pathway include 15-dPGJ<sub>2</sub> (see [[Cyclopentenone prostaglandin]]); '''d)''' [[Thromboxane synthase]] which converts PGH<sub>2</sub> to TXA<sub>2</sub> (subsequent products in this pathway include TXB<sub>2</sub>); and '''e)''' [[Prostacyclin synthase]] which converts PGH<sub>2</sub> to PGI<sub>2</sub> (subsequent products in this pathway include 6-keto-PGFα.<ref name="pmid25343148">{{Cite journal |vauthors=Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D |year=2014 |title=Cyclooxygenase pathways |journal=Acta Biochimica Polonica |volume=61 |issue=4 |pages=639–649 |doi=10.18388/abp.2014_1825 |pmid=25343148 |doi-access=free}}</ref><ref name="pmid25541289">{{Cite journal |vauthors=Claar D, Hartert TV, Peebles RS |year=2015 |title=The role of prostaglandins in allergic lung inflammation and asthma |journal=Expert Review of Respiratory Medicine |volume=9 |issue=1 |pages=55–72 |doi=10.1586/17476348.2015.992783 |pmc=4380345 |pmid=25541289}}</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. PGE<sub>3</sub> instead of PGE<sub>2</sub>).<ref name="pmid20558833">{{Cite journal |vauthors=Simopoulos AP |year=2010 |title=Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk |journal=Experimental Biology and Medicine |volume=235 |issue=7 |pages=785–795 |doi=10.1258/ebm.2010.009298 |pmid=20558833 |s2cid=207195131}}</ref>

The PGE<sub>2</sub>, PGE<sub>1</sub>, and PGD<sub>2</sub> products formed in the pathways just cited can undergo a spontaneous [[dehydration reaction]] to form PGA<sub>2</sub>, PGA<sub>1</sub>, and PGJ<sub>2</sub>, respectively; PGJ<sub>2</sub> may then undergo a spontaneous isomerization followed by a dehydration reaction to form in series Δ12-PGJ<sub>2</sub> and 15-deoxy-Δ12,14-PGJ<sub>2</sub>.<ref name="pmid21843512">{{Cite journal |vauthors=Surh YJ, Na HK, Park JM, Lee HN, Kim W, Yoon IS, Kim DD |year=2011 |title=15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling |journal=Biochemical Pharmacology |volume=82 |issue=10 |pages=1335–1351 |doi=10.1016/j.bcp.2011.07.100 |pmid=21843512}}</ref>

PGH<sub>2</sub> 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 A<sub>2</sub> 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 ===
{{See also|Leukotriene#Synthesis|Hydroxyeicosatetraenoic acid|Eoxin#Function}}

The enzyme [[5-lipoxygenase]] (5-LO or ALOX5) converts [[arachidonic acid]] into [[5-hydroperoxyeicosatetraenoic acid]] (5-HPETE), which may be released and rapidly [[redox|reduced]] to [[5-hydroxyeicosatetraenoic acid]] (5-HETE) by ubiquitous cellular [[glutathione]]-dependent [[peroxidase]]s.<ref>{{Cite journal |last1=Powell |first1=W. S. |last2=Rokach |first2=J |year=2013 |title=The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor |journal=Progress in Lipid Research |volume=52 |issue=4 |pages=651–665 |doi=10.1016/j.plipres.2013.09.001 |pmc=5710732 |pmid=24056189}}</ref>  Alternately, ALOX5 uses its LTA synthase activity to act convert 5-HPETE to [[Leukotriene A4|leukotriene A<sub>4</sub>]] (LTA<sub>4</sub>). LTA<sub>4</sub> is then metabolized either to LTB<sub>4</sub> by [[Leukotriene-A4 hydrolase|leukotriene A<sub>4</sub> hydrolase]] or [[Leukotriene C4|leukotriene C<sub>4</sub>]] (LTC<sub>4</sub>) by either [[LTC4 synthase|LTC<sub>4</sub> 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 LTA<sub>4</sub> thereby forming LTC<sub>4</sub>. After release from its parent cell, the glutamate and glycine residues of LTC<sub>4</sub> are removed step-wise by [[gamma-glutamyltransferase]] and a dipeptidase to form sequentially [[LTD4|LTD<sub>4</sub>]] and [[LTE4|LTE<sub>4</sub>]].<ref name="Rådmark_2015">{{Cite journal |vauthors=Rådmark O, Werz O, Steinhilber D, Samuelsson B |year=2015 |title=5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1851 |issue=4 |pages=331–339 |doi=10.1016/j.bbalip.2014.08.012 |pmid=25152163}}</ref><ref name="pmid26066610">{{Cite journal |vauthors=Ahmad S, Thulasingam M, Palombo I, Daley DO, Johnson KA, Morgenstern R, Haeggström JZ, Rinaldo-Matthis A |year=2015 |title=Trimeric microsomal glutathione transferase 2 displays one third of the sites reactivity |journal=Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics |volume=1854 |issue=10 Pt A |pages=1365–1371 |doi=10.1016/j.bbapap.2015.06.003 |pmid=26066610}}</ref> The decision to form LTB<sub>4</sub> versus LTC<sub>4</sub> depends on the relative content of LTA<sub>4</sub> hydrolase versus LTC<sub>4</sub> synthase (or glutathione S-transferase in cells; [[eosinophil]]s, [[mast cell]]s, and [[Pulmonary alveolus|alveolar]] [[macrophage]]s possess relatively high levels of LTC<sub>4</sub> synthase and accordingly form LTC<sub>4</sub> rather than or to a far greater extent than LTB<sub>4</sub>. 5-LOX may also work in series with cytochrome P450 oxygenases or aspirin-treated COX2 to form Resolvins RvE1, RvE2, and 18S-RvE1 (see {{slink|Specialized pro-resolving mediators|EPA-derived resolvins}}).

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 [[hepoxilin]]s (Hx) such as HxA3 and HxB.<ref>{{Cite journal |last=Pace-Asciak |first=C. R. |year=2009 |title=The hepoxilins and some analogues: A review of their biology |journal=British Journal of Pharmacology |volume=158 |issue=4 |pages=972–981 |doi=10.1111/j.1476-5381.2009.00168.x |pmc=2785520 |pmid=19422397}}</ref><ref>{{Cite journal |last1=Dobrian |first1=A. D. |last2=Lieb |first2=D. C. |last3=Cole |first3=B. K. |last4=Taylor-Fishwick |first4=D. A. |last5=Chakrabarti |first5=S. K. |last6=Nadler |first6=J. L. |year=2011 |title=Functional and pathological roles of the 12- and 15-lipoxygenases |journal=Progress in Lipid Research |volume=50 |issue=1 |pages=115–131 |doi=10.1016/j.plipres.2010.10.005 |pmc=3012140 |pmid=20970452}}</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>{{Cite journal |last1=Ivanov |first1=I |last2=Kuhn |first2=H |last3=Heydeck |first3=D |year=2015 |title=Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15) |journal=Gene |volume=573 |issue=1 |pages=1–32 |doi=10.1016/j.gene.2015.07.073 |pmc=6728142 |pmid=26216303}}</ref><ref>{{Cite journal |last1=Wittwer |first1=J |last2=Hersberger |first2=M |year=2007 |title=The two faces of the 15-lipoxygenase in atherosclerosis |journal=Prostaglandins, Leukotrienes and Essential Fatty Acids |volume=77 |issue=2 |pages=67–77 |doi=10.1016/j.plefa.2007.08.001 |pmid=17869078}}</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 {{slink|Specialized pro-resolving mediators|EPA-derived resolvins}}).

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">{{Cite journal |vauthors=Kroetz DL, Xu F |year=2005 |title=Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation |journal=Annual Review of Pharmacology and Toxicology |volume=45 |pages=413–438 |doi=10.1146/annurev.pharmtox.45.120403.100045 |pmid=15822183}}</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 acid]]s (EETs) by converting one of the fatty acid's [[double bond]]s 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">{{Cite journal |last1=Yang |first1=L |last2=Mäki-Petäjä |first2=K |last3=Cheriyan |first3=J |last4=McEniery |first4=C |last5=Wilkinson |first5=I. B. |year=2015 |title=The role of epoxyeicosatrienoic acids in the cardiovascular system |journal=British Journal of Clinical Pharmacology |volume=80 |issue=1 |pages=28–44 |doi=10.1111/bcp.12603 |pmc=4500322 |pmid=25655310}}</ref><ref name="Apr 2014">{{Cite journal |last1=Spector |first1=A. A. |last2=Kim |first2=H. Y. |year=2015 |title=Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1851 |issue=4 |pages=356–365 |doi=10.1016/j.bbalip.2014.07.020 |pmc=4314516 |pmid=25093613}}</ref>  14,15-EET and 11,12-EET are the major EETs produced by mammalian, including human, tissues.<ref name="Apr 2014" /><ref>{{Cite journal |last1=Fer |first1=M |last2=Dréano |first2=Y |last3=Lucas |first3=D |last4=Corcos |first4=L |last5=Salaün |first5=J. P. |last6=Berthou |first6=F |last7=Amet |first7=Y |year=2008 |title=Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450 |journal=Archives of Biochemistry and Biophysics |volume=471 |issue=2 |pages=116–125 |doi=10.1016/j.abb.2008.01.002 |pmid=18206980}}</ref><ref name="Pharmacol Ther 2014">{{Cite journal |last1=Shahabi |first1=P |last2=Siest |first2=G |last3=Meyer |first3=UA |last4=Visvikis-Siest |first4=S |year=2014 |title=Human cytochrome P450 epoxygenases: Variability in expression and role in inflammation-related disorders |journal=Pharmacology & Therapeutics |volume=144 |issue=2 |pages=134–161 |doi=10.1016/j.pharmthera.2014.05.011 |pmid=24882266}}</ref><ref>{{Cite journal |last1=Frömel |first1=T |last2=Kohlstedt |first2=K |last3=Popp |first3=R |last4=Yin |first4=X |last5=Awwad |first5=K |last6=Barbosa-Sicard |first6=E |last7=Thomas |first7=AC |last8=Lieberz |first8=R |last9=Mayr |first9=M |last10=Fleming |first10=I |year=2013 |title=Cytochrome P4502S1: A novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques |journal=Basic Research in Cardiology |volume=108 |issue=1 |page=319 |doi=10.1007/s00395-012-0319-8 |pmid=23224081 |s2cid=9158244}}</ref><ref>{{Cite journal |last=Fleming |first=I |year=2014 |title=The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease |journal=Pharmacological Reviews |volume=66 |issue=4 |pages=1106–1140 |doi=10.1124/pr.113.007781 |pmid=25244930 |s2cid=39465144}}</ref> The same CYPs but also CYP4A1, CYP4F8, and CYP4F12 metabolize [[eicosapentaenoic acid]] to five epoxide [[epoxyeicosatetraenoic acid]]s (EEQs) viz., 17,18-EEQ, 14,15-EEQ, 11,12-EEQ. 8,9-EEQ, and 5,6-EEQ.<ref>{{Cite journal |last1=Westphal |first1=C |last2=Konkel |first2=A |last3=Schunck |first3=WH |year=2011 |title=CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? |journal=Prostaglandins & Other Lipid Mediators |volume=96 |issue=1–4 |pages=99–108 |doi=10.1016/j.prostaglandins.2011.09.001 |pmid=21945326}}</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.

{| class="wikitable"
|-
! Eicosanoid !! Targeted receptors !! Functions regulated !! Clinical relevancy  
|-
| PGE<sub>2</sub> || [[PTGER1]], [[PTGER2]], [[PTGER3]], [[PTGER4]] || inflammation; fever; pain perception; [[allodynia]]; [[parturition]] || [[NSAID]]s inhibit its production to reduce inflammation, fever, and pain; used to promote labor in childbirth; an [[abortifacient]]<ref name="pmid25541289" /><ref name="pmid17767353">{{Cite journal |vauthors=Matsuoka T, Narumiya S |year=2007 |title=Prostaglandin receptor signaling in disease |journal=TheScientificWorldJournal |volume=7 |pages=1329–1347 |doi=10.1100/tsw.2007.182 |pmc=5901339 |pmid=17767353 |doi-access=free }}</ref><ref name="pmid24941907">{{Cite journal |vauthors=Thomas J, Fairclough A, Kavanagh J, Kelly AJ |year=2014 |title=Vaginal prostaglandin (PGE2 and PGF2a) for induction of labour at term |journal=The Cochrane Database of Systematic Reviews |volume=2014 |issue=6 |article-number=CD003101 |doi=10.1002/14651858.CD003101.pub3 |pmc=7138281 |pmid=24941907}}</ref>
|-
| PGD<sub>2</sub> || [[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">{{Cite journal |vauthors=Rossi A, Anzalone A, Fortuna MC, Caro G, Garelli V, Pranteda G, Carlesimo M |year=2016 |title=Multi-therapies in androgenetic alopecia: review and clinical experiences |journal=Dermatologic Therapy |volume=29 |issue=6 |pages=424–432 |doi=10.1111/dth.12390 |pmid=27424565 |hdl-access=free |hdl=11573/877469 |s2cid=45963890}}</ref><ref name="pmid22440736">{{Cite journal |vauthors=Garza LA, Liu Y, Yang Z, Alagesan B, Lawson JA, Norberg SM, Loy DE, Zhao T, Blatt HB, Stanton DC, Carrasco L, Ahluwalia G, Fischer SM, FitzGerald GA, Cotsarelis G |year=2012 |title=Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia |journal=Science Translational Medicine |volume=4 |issue=126 |pages=126ra34 |doi=10.1126/scitranslmed.3003122 |pmc=3319975 |pmid=22440736}}</ref><ref name="pmid15369681">{{Cite journal |vauthors=Hata AN, Breyer RM |year=2004 |title=Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation |journal=Pharmacology & Therapeutics |volume=103 |issue=2 |pages=147–166 |doi=10.1016/j.pharmthera.2004.06.003 |pmid=15369681}}</ref><ref name="pmid26748744">{{Cite journal |vauthors=Figueiredo-Pereira ME, Corwin C, Babich J |year=2016 |title=Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration |journal=Annals of the New York Academy of Sciences |volume=1363 |issue=1 |pages=125–137 |bibcode=2016NYASA1363..125F |doi=10.1111/nyas.12987 |pmc=4801700 |pmid=26748744}}</ref>
|-
| TXA<sub>2</sub> || [[Thromboxane receptor]] α and β || blood [[platelet]] aggregation; blood clotting; allergic reactions || NSAIDs inhibit its production to reduce incidence of [[stroke]]s and [[heart attack]]s<ref name="pmid25541289" /><ref name="pmid26621246">{{Cite journal |vauthors=Hoxha M, Buccellati C, Capra V, Garella D, Cena C, Rolando B, Fruttero R, Carnevali S, Sala A, Rovati GE, Bertinaria M |year=2016 |title=In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition |url=https://iris.unito.it/retrieve/handle/2318/1551575/113257/Pharmacol%20res%20_open_access.pdf |journal=Pharmacological Research |volume=103 |pages=132–143 |doi=10.1016/j.phrs.2015.11.012 |pmid=26621246 |hdl=2318/1551575|s2cid=12881002 }}</ref>
|-
| PGI<sub>2</sub> || [[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">{{Cite journal |vauthors=Cruz JE, Ward A, Anthony S, Chang S, Bae HB, Hermes-DeSantis ER |year=2016 |title=Evidence for the Use of Epoprostenol to Treat Raynaud's Phenomenon With or Without Digital Ulcers: A Review of the Literature |journal=The Annals of Pharmacotherapy |volume=50 |issue=12 |pages=1060–1067 |doi=10.1177/1060028016660324 |pmid=27465880 |s2cid=38333954}}</ref><ref name="pmid26748508">{{Cite journal |vauthors=O'Connell C, Amar D, Boucly A, Savale L, Jaïs X, Chaumais MC, Montani D, Humbert M, Simonneau G, Sitbon O |year=2016 |title=Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension |journal=Drug Safety |volume=39 |issue=4 |pages=287–294 |doi=10.1007/s40264-015-0365-x |pmid=26748508 |s2cid=24852012}}</ref><ref>{{Cite journal |last1=Cacione |first1=Daniel G. |last2=Macedo |first2=Cristiane R. |last3=do Carmo Novaes |first3=Frederico |last4=Baptista-Silva |first4=Jose Cc |date=4 May 2020 |title=Pharmacological treatment for Buerger's disease |journal=The Cochrane Database of Systematic Reviews |volume=5 |issue=5 |article-number=CD011033 |doi=10.1002/14651858.CD011033.pub4 |issn=1469-493X |pmc=7197514 |pmid=32364620}}</ref>

|-
| 15-d-Δ12,14-PGJ<sub>2</sub> || [[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">{{Cite journal |vauthors=Citterio A, Arnoldi A, Panzeri E, D'Angelo MG, Filosto M, Dilena R, Arrigoni F, Castelli M, Maghini C, Germiniasi C, Menni F, Martinuzzi A, Bresolin N, Bassi MT |year=2014 |title=Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis |url=https://air.unimi.it/bitstream/2434/421160/2/Citterio%20J%20Neurol%202014.pdf |journal=Journal of Neurology |volume=261 |issue=2 |pages=373–381 |doi=10.1007/s00415-013-7206-6 |pmid=24337409 |hdl=2434/421160 |s2cid=19189811}}</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" />
|-
| LTB<sub>4</sub> || [[LTB4R]], [[LTB4R2]] || chemotactic factor for and activator of leukocytes; inflammation || studies to date shown no clear benefits of LTB<sub>4</sub> receptor antagonists for human inflammatory diseases<ref name="pmid25572555">{{Cite journal |vauthors=Liu M, Yokomizo T |year=2015 |title=The role of leukotrienes in allergic diseases |journal=Allergology International |volume=64 |issue=1 |pages=17–26 |doi=10.1016/j.alit.2014.09.001 |pmid=25572555 |doi-access=free}}</ref><ref name="pmid21771892">{{Cite journal |vauthors=Bäck M, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE |year=2011 |title=International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions |journal=Pharmacological Reviews |volume=63 |issue=3 |pages=539–584 |doi=10.1124/pr.110.004184 |pmid=21771892 |doi-access=free |s2cid=5563700}}</ref><ref name="pmid24588652">{{Cite journal |vauthors=Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE |year=2014 |title=Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7 |journal=British Journal of Pharmacology |volume=171 |issue=15 |pages=3551–3574 |doi=10.1111/bph.12665 |pmc=4128057 |pmid=24588652}}</ref>
|-
| LTC<sub>4</sub> ||[[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">{{Cite journal |vauthors=Cingi C, Muluk NB, Ipci K, Şahin E |year=2015 |title=Antileukotrienes in upper airway inflammatory diseases |journal=Current Allergy and Asthma Reports |volume=15 |issue=11 |article-number=64 |doi=10.1007/s11882-015-0564-7 |pmid=26385352 |s2cid=38854822}}</ref><ref name="pmid20886028">{{Cite journal |vauthors=Nettis E, D'Erasmo M, Di Leo E, Calogiuri G, Montinaro V, Ferrannini A, Vacca A |year=2010 |title=The employment of leukotriene antagonists in cutaneous diseases belonging to allergological field |journal=Mediators of Inflammation |volume=2010 |pages=1–6 |doi=10.1155/2010/628171 |pmc=2945673 |pmid=20886028 |doi-access=free}}</ref>
|-
| LTD<sub>4</sub> || [[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" />
|-
| LTE<sub>4</sub> || [[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">{{Cite journal |vauthors=Kanaoka Y, Maekawa A, Austen KF |year=2013 |title=Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand |journal=The Journal of Biological Chemistry |volume=288 |issue=16 |pages=10967–10972 |doi=10.1074/jbc.C113.453704 |pmc=3630866 |pmid=23504326 |doi-access=free}}</ref>
|-
| LxA<sub>4</sub> || [[FPR2]] || inhibits functions of pro-inflammatory cells || Specialized pro-resolving mediators class of inflammatory reaction suppressors<ref name="pmid25895638">{{Cite journal |vauthors=Romano M, Cianci E, Simiele F, Recchiuti A |year=2015 |title=Lipoxins and aspirin-triggered lipoxins in resolution of inflammation |journal=European Journal of Pharmacology |volume=760 |pages=49–63 |doi=10.1016/j.ejphar.2015.03.083 |pmid=25895638}}</ref><ref name="pmid16968948">{{Cite journal |vauthors=Chiang N, Serhan CN, Dahlén SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C |year=2006 |title=The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo |journal=Pharmacological Reviews |volume=58 |issue=3 |pages=463–487 |doi=10.1124/pr.58.3.4 |pmid=16968948 |s2cid=6496181}}</ref>
|-
| LxB<sub>4</sub> || [[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">{{Cite journal |vauthors=Qu Q, Xuan W, Fan GH |year=2015 |title=Roles of resolvins in the resolution of acute inflammation |journal=Cell Biology International |volume=39 |issue=1 |pages=3–22 |doi=10.1002/cbin.10345 |pmid=25052386 |s2cid=10160642}}</ref><ref name="pmid26339646">{{Cite journal |vauthors=Lim JY, Park CK, Hwang SW |year=2015 |title=Biological Roles of Resolvins and Related Substances in the Resolution of Pain |journal=BioMed Research International |volume=2015 |article-number=830930 |doi=10.1155/2015/830930 |pmc=4538417 |pmid=26339646 |doi-access=free}}</ref><ref name="pmid25359497">{{Cite journal |vauthors=Serhan CN, Chiang N, Dalli J, Levy BD |year=2015 |title=Lipid mediators in the resolution of inflammation |journal=Cold Spring Harbor Perspectives in Biology |volume=7 |issue=2 |article-number=a016311 |doi=10.1101/cshperspect.a016311 |pmc=4315926 |pmid=25359497}}</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">{{Cite journal |vauthors=Serhan CN, Chiang N |year=2013 |title=Resolution phase lipid mediators of inflammation: agonists of resolution |journal=Current Opinion in Pharmacology |volume=13 |issue=4 |pages=632–640 |doi=10.1016/j.coph.2013.05.012 |pmc=3732499 |pmid=23747022}}</ref>
|-
| 14,15-EET || ? || [[vasodilation]], inhibits platelets and pro-inflammatory cells || role(s) in human disease not yet proven<ref name="pmid25655310">{{Cite journal |vauthors=Yang L, Mäki-Petäjä K, Cheriyan J, McEniery C, Wilkinson IB |year=2015 |title=The role of epoxyeicosatrienoic acids in the cardiovascular system |journal=British Journal of Clinical Pharmacology |volume=80 |issue=1 |pages=28–44 |doi=10.1111/bcp.12603 |pmc=4500322 |pmid=25655310}}</ref><ref>{{ClinicalTrialsGov|NCT00847899|Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance}}</ref>
|}

===Prostanoids===
{{main article|Prostaglandin|Prostacyclin|Thromboxane}}
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 [[NSAID]]s (non-steroidal anti-inflammatory drugs), such as [[aspirin]]. Prostanoids also activate the PPAR<sub>γ</sub> members of the steroid/thyroid family of [[Nuclear receptor|nuclear hormone receptors]], and directly influence [[Transcription (biology)|gene transcription]].<ref name="Bos">{{Cite journal |vauthors=Bos C, Richel D, Ritsema T, Peppelenbosch M, Versteeg H |year=2004 |title=Prostanoids and prostanoid receptors in signal transduction |journal=Int J Biochem Cell Biol |volume=36 |issue=7 |pages=1187–1205 |doi=10.1016/j.biocel.2003.08.006 |pmid=15109566}}</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.

{| class="wikitable"
|-
! Medicine !! Type !! Medical condition or use !! !! Medicine !! Type !! Medical condition or use 
|-
| [[Alprostadil]] || [[PGE1|PGE<sub>1</sub>]] || [[Erectile dysfunction]], maintaining a [[patent ductus arteriosus]] in the [[fetus]] || || [[Beraprost]] || PGI<sub>2</sub> analog || [[Pulmonary hypertension]], avoiding [[reperfusion injury]]
|-
| [[Bimatoprost]] || PGF<sub>2α</sub> analog || [[Glaucoma]], [[ocular hypertension]] || || [[Carboprost]]  || PGF<sub>2α</sub> analog ||  Labor induction, abortifacient in early pregnancy
|-
| [[Dinoprostone]] || PGE<sub>2</sub> || Labor induction || || [[Iloprost]] || PGI<sub>2</sub> analog || [[Pulmonary artery hypertension]]
|-
| [[Latanoprost]] || PGF<sub>2α</sub> analog || [[Glaucoma]], [[ocular hypertension]] || || [[Misoprostol]] || PGE<sub>1</sub> analog || [[Stomach ulcer]]s [[labor induction]], [[abortifacient]]
|-
| [[Travoprost]] || PGF<sub>2α</sub> analog || [[Glaucoma]], [[ocular hypertension]] || || [[U46619]] || Longer lived TX analog || Research only 
|-
|}

===Cyclopentenone prostaglandins===
{{main article|Cyclopentenone prostaglandins}}
PGA<sub>1</sub>, PGA<sub>2</sub>, PGJ<sub>2</sub>, Δ12-PGJ<sub>2</sub>, and 15-deox-Δ12,14-PGJ<sub>2</sub> 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===
{{main article|5-Hydroxyeicosatetraenoic acid|5-Oxo-eicosatetraenoic acid|12-Hydroxyeicosatetraenoic acid|15-Hydroxyeicosatetraenoic acid|20-Hydroxyeicosatetraenoic acid}}
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===
{{main article|Leukotriene}}
The three cysteinyl leukotrienes, LTC<sub>4</sub>, LTD<sub>4</sub>, and LTE<sub>4</sub>, are potent bronchoconstrictors, increasers of vascular permeability in postcapillary [[venule]]s, 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 [[Allergy|immediate hypersensitivity]] reactions.<ref name="Samuelsson83">{{Cite journal |last=Samuelsson B |date=May 1983 |title=Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation |journal=Science |volume=220 |issue=4597 |pages=568–575 |bibcode=1983Sci...220..568S |doi=10.1126/science.6301011 |pmid=6301011}}</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 {{slink|Acquired non-inflammatory myopathy|Diet and Trauma Induced Myopathy}}).<ref name="pmid21936577">{{Cite journal |vauthors=Haeggström JZ, Funk CD |year=2011 |title=Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease |url=https://zenodo.org/record/3424215 |journal=Chemical Reviews |volume=111 |issue=10 |pages=5866–5898 |doi=10.1021/cr200246d |pmid=21936577 }}{{Dead link|date=February 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid24313690">{{Cite journal |vauthors=Anwar Y, Sabir JS, Qureshi MI, Saini KS |year=2014 |title=5-lipoxygenase: a promising drug target against inflammatory diseases-biochemical and pharmacological regulation |journal=Current Drug Targets |volume=15 |issue=4 |pages=410–422 |doi=10.2174/1389450114666131209110745 |pmid=24313690}}</ref><ref name="pmid26980339">{{Cite journal |vauthors=Kar M, Altıntoprak N, Muluk NB, Ulusoy S, Bafaqeeh SA, Cingi C |date=March 2016 |title=Antileukotrienes in adenotonsillar hypertrophy: a review of the literature |journal=European Archives of Oto-Rhino-Laryngology |volume=273 |issue=12 |pages=4111–4117 |doi=10.1007/s00405-016-3983-8 |pmid=26980339 |s2cid=31311115}}</ref><ref name="pmid26678823">{{Cite journal |vauthors=Oussalah A, Mayorga C, Blanca M, Barbaud A, Nakonechna A, Cernadas J, Gotua M, Brockow K, Caubet JC, Bircher A, Atanaskovic M, Demoly P, K Tanno L, Terreehorst I, Laguna JJ, Romano A, Guéant JL |date=April 2016 |title=Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review |url=https://archive-ouverte.unige.ch/unige:83795/ATTACHMENT01 |journal=Allergy |volume=71 |issue=4 |pages=443–462 |doi=10.1111/all.12821 |pmid=26678823 |doi-access=free |s2cid=13352894}}</ref> When combined with [[antihistamine]] drug therapy, they also appear useful for treating [[urticaria]]l diseases such as hives.<ref name="pmid25515967">{{Cite journal |vauthors=Mitchell S, Balp MM, Samuel M, McBride D, Maurer M |year=2015 |title=Systematic review of treatments for chronic spontaneous urticaria with inadequate response to licensed first-line treatments |journal=International Journal of Dermatology |volume=54 |issue=9 |pages=1088–1104 |doi=10.1111/ijd.12727 |pmid=25515967 |s2cid=23250789}}</ref>

===Lipoxins and epi-lipoxins===
{{main article|Lipoxin}}
LxA<sub>4</sub>, LxB<sub>4</sub>, 15-epi-LxA<sub>4</sub>, and 15-epi-LXB<sub>4</sub>, 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-LXA<sub>4</sub> and a comparatively stable analog of LXB<sub>4</sub>, 15''R/S''-methyl-LXB<sub>4</sub>, reduced the severity of [[eczema]] in a study of 60 infants<ref name="pmid22834636">{{Cite journal |vauthors=Wu SH, Chen XQ, Liu B, Wu HJ, Dong L |year=2013 |title=Efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in topical treatment of infantile eczema |journal=The British Journal of Dermatology |volume=168 |issue=1 |pages=172–178 |doi=10.1111/j.1365-2133.2012.11177.x |pmid=22834636 |s2cid=31721094}}</ref> and, in another study, inhaled LXA<sub>4</sub> decreased LTC<sub>4</sub>-initiated bronchoprovocation in patients with asthma.<ref name="pmid26688348">{{Cite journal |vauthors=Basil MC, Levy BD |year=2016 |title=Specialized pro-resolving mediators: endogenous regulators of infection and inflammation |journal=Nature Reviews. Immunology |volume=16 |issue=1 |pages=51–67 |doi=10.1038/nri.2015.4 |pmc=5242505 |pmid=26688348}}</ref>

===Eoxins===
{{main article|Eoxin}}
The eoxins (EXC<sub>4</sub>, EXD<sub>4</sub>, EXE<sub>5</sub>) are newly described. They stimulate vascular permeability in an ex vivo human vascular endothelial model system,<ref name="Primary eosinophils and mast cells">{{Cite journal |vauthors=Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE |date=January 2008 |title=Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=105 |issue=2 |pages=680–685 |bibcode=2008PNAS..105..680F |doi=10.1073/pnas.0710127105 |pmc=2206596 |pmid=18184802 |doi-access=free}}</ref> and in a small study of 32 volunteers EXC<sub>4</sub> 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">{{Cite journal |vauthors=James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE |year=2013 |title=The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma |journal=Int. Arch. Allergy Immunol. |volume=162 |issue=2 |pages=135–142 |doi=10.1159/000351422 |pmid=23921438 |s2cid=29180895}}</ref> Production of eoxins by Reed–Sternberg cells cells has also led to suggestion that they are involved in [[Hodgkins disease]].<ref name="pmid19130894">{{Cite journal |vauthors=Claesson HE |year=2009 |title=On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma |journal=Prostaglandins & Other Lipid Mediators |volume=89 |issue=3–4 |pages=120–125 |doi=10.1016/j.prostaglandins.2008.12.003 |pmid=19130894}}</ref> However, the clinical significance of eoxins has not yet been demonstrated.

===Resolvin metabolites of eicosapentaenoic acid===
{{main article|Resolvin}}
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">{{Cite journal |vauthors=Serhan CN, Chiang N, Dalli J |year=2015 |title=The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution |journal=Seminars in Immunology |volume=27 |issue=3 |pages=200–215 |doi=10.1016/j.smim.2015.03.004 |pmc=4515371 |pmid=25857211}}</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. PGE<sub>3</sub>, PGD<sub>3</sub>, PGF<sub>3α</sub>, PGI<sub>3</sub>, and TXA<sub>3</sub>), the hydroxyeicosapentaenoic acids (e.g. 5-HEPE, 12-HEPE, 15-HEPE, and 20-HEPE), and the 5-series LTs (e.g. LTB<sub>5</sub>, LTC<sub>5</sub>, LTD<sub>5</sub>, and LTE<sub>5</sub>). 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">{{Cite journal |vauthors=Guichardant M, Calzada C, Bernoud-Hubac N, Lagarde M, Véricel E |year=2015 |title=Omega-3 polyunsaturated fatty acids and oxygenated metabolism in atherothrombosis |url=http://www.hal.inserm.fr/inserm-01072309/document |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1851 |issue=4 |pages=485–495 |doi=10.1016/j.bbalip.2014.09.013 |pmid=25263947}}</ref><ref name="pmid25008763">{{Cite journal |vauthors=Calder PC |year=2014 |title=Biomarkers of immunity and inflammation for use in nutrition interventions: International Life Sciences Institute European Branch work on selection criteria and interpretation |journal=Endocrine, Metabolic & Immune Disorders Drug Targets |volume=14 |issue=4 |pages=236–244 |doi=10.2174/1871530314666140709091650 |pmid=25008763}}</ref> Eicosapentaenoic acid-derived counterparts of the eoxins have not been described.

===Epoxyeicosanoids===
{{main article|Epoxyeicosatrienoic acid|Epoxyeicosatetraenoic acid}}
The epoxy eicosatrienoic acids (or EETs)—and, presumably, the epoxy eicosatetraenoic acids—have [[Vasodilation|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 [[Ischemia|ischemic]] and other injuries to the heart, [[brain]], and other [[Tissue (biology)|tissue]]s; they may also act to reduce inflammation, promote the growth and [[metastasis]] of certain [[tumor]]s, promote the growth of new blood vessels, in the [[central nervous system]], regulate the release of [[neuropeptide]] [[hormone]]s, 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 ==
{{main article|Essential fatty acid interactions}}
{{Cquote|The reduction in AA-derived eicosanoids and the diminished activity of the alternative products generated from ω-3 fatty acids serve as the foundation for explaining some of the beneficial effects of greater ω-3 intake.|40px|40px|Kevin Fritsche|Fatty Acids as Modulators of the Immune Response<ref name="Fritsche" />}}
[[Arachidonic acid]] (AA; 20:4 ω−6)  sits at the head of the "arachidonic acid cascade" – more than twenty eicosanoid-mediated [[cell signaling|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.  [[Eicosapentaenoic acid|EPA (20:5 ω−3)]] provides the most important competing cascade. [[Dihomo-gamma-linolenic acid|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 illness]]es.

The U.S. [[National Institutes of Health]] and the [[National Library of Medicine]] state that there is [[Evidence-based medicine#Assessing the quality of evidence|'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 [[Preventive healthcare|primary prevention]] of cardiovascular disease, [[rheumatoid arthritis]], and protection from [[ciclosporin]] toxicity in [[Organ transplantation|organ transplant]] patients.
They also note more preliminary evidence showing that dietary ω−3 can ease symptoms in several psychiatric disorders.<ref name="National">{{Cite web |last=National Institute of Health |date=2005-08-01 |title=Omega-3 fatty acids, fish oil, alpha-linolenic acid |url=https://www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-fishoil.html |archive-url=https://web.archive.org/web/20060503222604/http://www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-fishoil.html |archive-date=May 3, 2006 |access-date=March 26, 2006}}</ref>

Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They
(a) alter [[membrane fluidity|membrane composition and function]], including the composition of [[lipid raft]]s;
(b) change [[cytokine]] biosynthesis; and (c) directly activate gene transcription.<ref name="Fritsche">{{Cite journal |last=Fritsche |first=Kevin |date=August 2006 |title=Fatty Acids as Modulators of the Immune Response |journal=Annual Review of Nutrition |volume=26 |pages=45–73 |doi=10.1146/annurev.nutr.25.050304.092610 |pmid=16848700}}</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|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>{{Cite web |last=Thompson |first=Dennis |date=2024-08-02 |title=Fish Oil Might Help High-Risk Older Adults Avoid Alzheimer's |url=https://www.healthday.com/health-news/neurology/fish-oil-might-help-high-risk-older-adults-avoid-alzheimers |access-date=2024-08-06 |website=www.healthday.com |language=en}}</ref><ref>{{Cite journal |last1=Shinto |first1=Lynne H. |last2=Murchison |first2=Charles F. |last3=Silbert |first3=Lisa C. |last4=Dodge |first4=Hiroko H. |last5=Lahna |first5=David |last6=Rooney |first6=William |last7=Kaye |first7=Jeffrey |last8=Quinn |first8=Joseph F. |last9=Bowman |first9=Gene L. |date=2024-08-01 |title=ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial |journal=JAMA Network Open |volume=7 |issue=8 |pages=e2426872 |doi=10.1001/jamanetworkopen.2024.26872 |pmid=39088212 |issn=2574-3805|pmc=11294966 }}</ref>   
{{clear}}

===Mechanisms of ω−3 action===

[[File:EFA to Eicosanoids.svg|440px|thumb|right|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 [[Gamma-linolenic acid|GLA]] (''via'' DGLA) are less inflammatory, or inactive, or even anti-inflammatory and [[Inflammation#Resolution|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 ===
[[Aulus Cornelius Celsus|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.

''[[Erythema|Redness]]''—An insect's sting will trigger the classic inflammatory response. Short acting [[Vasoconstriction|vasoconstrictor]]s — TXA<sub>2</sub> — are released quickly after the injury. The site may momentarily turn pale. Then TXA<sub>2</sub> mediates the release of the [[Vasodilation|vasodilators]] PGE<sub>2</sub> and LTB<sub>4</sub>. The blood vessels engorge and the injury reddens.<br />
''[[Edema|Swelling]]''—LTB<sub>4</sub> makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also loses pro-inflammatory cytokines.<br />
''[[Hyperalgesia|Pain]]''—The [[cytokine]]s increase COX-2 activity. This elevates levels of PGE<sub>2</sub>, sensitizing pain neurons.<br />
''[[Fever|Heat]]''—PGE<sub>2</sub> 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 O. Burr|George]] and Mildred Burr showed that restricting fat from animals' diets led to a deficiency disease, and first described the [[essential fatty acid]]s.<ref name="Burr">{{Cite journal |last1=Burr, G.O. |last2=Burr, M.M. |year=1930 |title=On the nature and role of the fatty acids essential in nutrition |journal=J. Biol. Chem. |volume=86 |issue=587 |pages=587–621 |doi=10.1016/S0021-9258(20)78929-5 |doi-access=free}}</ref>
In 1935, [[Ulf von Euler|von Euler]] identified prostaglandin.
In 1964, [[Sune Bergström|Bergström]] and [[Bengt I. Samuelsson|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">{{Cite journal |last1=Bergström, S. |last2=Danielsson, H. |last3=Samuelsson, B. |year=1964 |title=The enzymatic formation of prostaglandin E2 from arachidonic acid |journal=Biochim. Biophys. Acta |volume=90 |issue=207 |pages=207–210 |doi=10.1016/0304-4165(64)90145-x |pmid=14201168}}</ref>
In 1971, [[John Robert Vane|Vane]] showed that aspirin and similar drugs inhibit prostaglandin synthesis.<ref name="Vane">{{Cite journal |last=Vane, J. R. |date=June 23, 1971 |title=Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs |journal=Nature New Biology |volume=231 |issue=25 |pages=232–235 |doi=10.1038/newbio231232a0 |pmid=5284360}}</ref>  Von Euler received the [[Nobel Prize]] in medicine in 1970, which
Samuelsson, Vane, and Bergström also received in 1982.
[[Elias James Corey|E. J. Corey]] received it in chemistry in 1990 largely for his synthesis of prostaglandins.

==See also==
*[[Eicosanoid receptor]]s

==References==
{{Reflist|30em}}

==External links==
* {{MeshName|Eicosanoids}}

{{Lipids}}
{{Eicosanoids}}
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[[Category:Eicosanoids| ]]