In biochemistry, eicosanoids are signaling molecules made by
oxygenationof twenty-carbon essential fatty acids, (EFAs).They exert complex control over many bodily systems, mainly in inflammationor immunity, and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body.
Eicosanoids derive from either omega-3 (ω-3) or omega-6 (ω-6) EFAs.The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on
cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such as aspirinand other NSAIDs act by downregulating eicosanoid synthesis.
There are four families of eicosanoids—the
prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. For each, there are two or three separate series, derived either from an ω-3 or ω-6 EFA. These series' different activities largely explain the health effects of ω-3 and ω-6 fats.cite journal
author=DeCaterina, R and Basta, G
journal= European Heart Journal Supplements
volume =3, Suppl D
title= n-3 Fatty acids and the inflammatory response – biological background
url = http://eurheartjsupp.oxfordjournals.org/cgi/reprint/3/suppl_D/D42.pdf
accessdate= 2006-02-10 |month=June | year=2001|format=PDF] cite journal
author=Funk, Colin D. | journal=Science |date=
30 November 2001
volume= 294| issue= 5548 |pages= 1871–1875 |doi = 10.1126/science.294.5548.1871
title= Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology
accessdate = 2007-01-08
pmid= 11729303] cite journal|author=Piomelli, Daniele |title=Arachidonic Acid
year= 2000|accessdate=2006-03-03|work=Neuropsychopharmacology: The Fifth Generation of Progress] cite journal
author=Soberman, Roy J. and Christmas, Peter
title =The organization and consequences of eicosanoid signaling
journal =J. Clin. Invest| volume= 111 |pages=1107–1113 |year=2003
url = http://www.jci.org/cgi/content/full/111/8/1107
doi = 10.1172/JCI200318338
accessdate = 2007-01-05]
:"See related detail at Essential Fatty Acid Interactions—Nomenclature"Eicosanoid" ("eicosa-", Greek for "twenty"; "see
icosahedron") is the collective termcite web
title=IUPAC Lexicon of Lipid Nutrition
accessmonthday=June 1 |accessyear=2006|format=PDF] for oxygenated derivatives of three different 20-carbon
essential fatty acids:
Eicosapentaenoic acid(EPA), an ω-3 fatty acid with 5 double bonds;
Arachidonic acid(AA), an ω-6 fatty acid, with 4 double bonds;
Dihomo-gamma-linolenic acid(DGLA), an ω-6, with 3 double bonds.Current usage limits the term to the leukotrienes (LT) and three types of prostanoids— prostaglandins (PG) prostacyclins (PGI), and thromboxanes (TX). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epi-lipoxins, epoxyeicosatrienoic acids (EETs) and endocannabinoids. LTs and prostanoids are sometimes termed 'classic eicosanoids'cite journal
author=Van Dyke TE, Serhan CN
title=Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases |journal=J. Dent. Res.
volume=82 |issue=2 |pages=82–90 |year=2003 |pmid=12562878 |doi=|accessdate=2007-10-28 ] cite journal |author=Serhan CN, Gotlinger K, Hong S, Arita M
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=155–72 |year=2004 |pmid=15290791
doi=|accessdate=2007-10-28] cite journal |author=Anderle P, Farmer P, Berger A, Roberts MA
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=103–8 |year=2004 |pmid=14698023
doi=|accessdate=2007-10-28 ] in contrast to the 'novel', 'eicosanoid-like' or '
nonclassic eicosanoids'. cite journal |author=Evans AR, Junger H, Southall MD, "et al" |title=Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons |journal=J. Pharmacol. Exp. Ther. |volume=293 |issue=3 |pages=912–20 |year=2000 |pmid=10869392 |doi=|accessdate=2007-10-28] cite journal |author=O'Brien WF, Krammer J, O'Leary TD, Mastrogiannis DS |title=The effect of acetaminophen on prostacyclin production in pregnant women |journal=Am. J. Obstet. Gynecol. |volume=168 |issue=4 |pages=1164–9 |year=1993 |pmid=8475962 |doi=] cite journal |author=Behrendt H, Kasche A, Ebner von Eschenbach C, Risse U, Huss-Marp J, Ring J |title=Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization |journal=Int. Arch. Allergy Immunol. |volume=124 |issue=1-3 |pages=121–5 |year=2001 |pmid=11306946 |doi=10.1159/000053688|accessdate=2007-11-02] cite journal |author=Sarau HM, Foley JJ, Schmidt DB, "et al" |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 |year=1999 |pmid=10477044 |doi=10.1054/plef.1999.0074|accessdate=2007-11-02] A particular eicosanoid is denoted by a four-character abbreviation, composed of:
* Its two letter abbreviation (above), [Prostacyclin—PGI—was previously classified as prostaglandin and retains its old identifier.]
*One A-B-C sequence-letter; Eicosanoids with different letters have placement of double-bonds and different
functional groups attached to the molecular skeleton. Letters indicate roughly the order the eicosanoids were first described in the literature. For diagrams for PG A–H see cite web| url= http://www.cyberlipid.org/prost1/pros0001.htm |author=Cyberlipid Center|title = Prostanoids|accessdate=2007-02-05 ] and
*A subscript, indicating the number of double bonds.Examples are:
* The EPA-derived prostanoids have three double bonds, (e.g. PGG3, PGH3, PGI3, TXA3) while its leukotrienes have five, (LTB5).
*The AA-derived prostanoids have two double bonds, (e.g. PGG2, PGH2, PGI2, TXA2) while its leukotrienes have four, (LTB4).
stereochemistrymay differ among the pathways, indicated by Greek letters, e.g. for (PGF2α).
Two families of
enzymescatalyze fatty acid oxygenation to produce the eicosanoids:
Cyclooxygenase, or COX, generates the prostanoids.
Lipoxygenase, or LOX, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes.
Eicosanoid biosynthesis begins when cell is activated by mechanical trauma,
cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) Phospholipaseis released at the cell membraneand travels to the nuclear membrane.There, it frees 20-carbon essential fatty acids. This event appears to be the rate-determining stepfor eicosanoid formation.
Next, the free fatty acid is oxygenated along any of several pathways; see the "Pathways" table. The classical pathways add molecular oxygen (O2) "via"
Lipoxygenaseor Cyclooxygenase. Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity.
Peroxidation and reactive oxygen species
The generation of eicosanoids is hazardous to the cell, particularly as it occurs close to the nucleus. Oxidation releases
reactive oxygen species(ROS). Further, the initial products in eicosanoid generation are themselves highly reactive peroxides. E.g., LTA4 can form adducts with tissue DNA. Lipoxygenase can generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesisof atherosclerosis.cite journal
journal= J Clin Invest
month= June | year= 1999 |volume = 103| number =11| pages= 1597–1604n
title=Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice
doi=10.1172/JCI5897] cite journal
author=Schewe T. |journal= Biol Chem. |year= 2002 Mar-Apr| volume= 383|issue= 3-4
title = 15-lipoxygenase-1: a prooxidant enzyme
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12033428
Nevertheless, there is an advantage in the proximity to the nucleus, since, PGs and LTs may signal or regulate DNA-transcription there; For instance, LTB4 is a
ligandfor PPARα,"(see diagram at PPAR)."
There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlled—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple
isoforms. Perhaps eicosanoid signaling evolved from the detoxification of ROS.Several of enzymes which are biosynthetic for eicosanoids belong to families whose functions are largely involved with cellular detoxification.
The ω-3 and ω-6 series
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 Responsecite journal
journal= Annual Review of Nutrition
volume= 26 |pages=45–73 |month= August | year= 2006
title= Fatty Acids as Modulators of the Immune Response
Arachidonic acid(AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'—more than twenty different eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity and the central nervous system.
In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. provides the most important competing cascade. 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 essential fatty acids, especially the ω-3s, has been linked to several inflammation-related diseases, and perhaps some
National Institutes of Healthand the National Library of Medicinestate that there is 'A' level evidence ('strong scientific evidence') that increased dietary ω-3 improves outcomes in hypertriglyceridemia, secondary cardiovascular diseaseprevention and hypertension.There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in primary prevention of cardiovascular disease, rheumatoid arthritisand protection from ciclosporin toxicity in organ transplantpatients.They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.cite web
author=National Institute of Health
title=Omega-3 fatty acids, fish oil, alpha-linolenic acid
accessmonthday=March 26 | accessyear=2006| date= 2005-08-01]
Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter membrane composition and function, including the composition of
lipid rafts;(b) change cytokinebiosynthesis and (c) directly activate gene transcription. Of these, the action on eicosanoids is the best explored.
Mechanisms of ω-3 action
The eicosanoids from AA generally promote inflammation. Those from EPA and from GLA ("via" DGLA) are generally less inflammatory, or inactive, or even anti-inflammatory.The figure shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA.
Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways, along the eicosanoid pathways:
*"Displacement"—Dietary ω-3 decreases tissue concentrations of AA, so there is less to form ω-6 eicosanoids.
*"Competitive inhibition"—DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosanoids.
*"Counteraction"—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts.
Role in inflammation
Since antiquity, the cardinal signs of inflammation have been known as: calor (warmth), dolor (pain), tumor (swelling) and rubor (redness). The eicosanoids are involved with each of these signs.
"Redness"—An insect's sting will trigger the classic inflammatory response. Short acting
vasoconstrictors — TXA2—are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the vasodilatorsPGE2 and LTB4. The blood vessels engorge and the injury reddens.
"Swelling"—LTB4 makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also looses pro-inflammatory cytokines.
"Pain"—The cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons.
"Heat"—PGE2 is also a potent pyretic agent. Aspirin and NSAIDS—drugs that block the COX pathways and stop prostanoid synthesis—limit fever or the heat of localized inflammation.
Action of prostanoids
Prostaglandin, Prostacyclinand Thromboxane"Prostanoids mediate local symptoms of inflammation: vasoconstrictionor vasodilation, coagulation, painand fever. Inhibition of cyclooxygenase, specifically the inducible COX-2 isoform, is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. COX-2 is responsible for pain and inflammation, while COX-1 is responsible for platelet clotting actions.
Prostanoids activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription.cite journal |author=Bos C, Richel D, Ritsema T, Peppelenbosch M, Versteeg H |title=Prostanoids and prostanoid receptors in signal transduction |journal=Int J Biochem Cell Biol |volume=36 |issue=7 |pages=1187–205 |year=2004 |pmid=15109566 |doi=10.1016/j.biocel.2003.08.006]
Action of leukotrienes
Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in
luteinizing hormonesecretion.cite journal|journal=Science |year= 1987|month=09-04 |volume= 237|number= 4819|pages=1171–1176
doi= 10.1126/science.2820055|title=Leukotrienes and lipoxins: structures, biosynthesis, and biological effects|author=Samuelsson, SE Dahlen, JA Lindgren, CA Rouzer, and CN Serhan |url=http://www.sciencemag.org/cgi/content/abstract/237/4819/1171|accessdate=2007-01-22|pmid=2820055] LTB4 causes adhesion and
chemotaxisof leukocytes and stimulates aggregation, enzyme release, and generation of superoxidein neutrophils.cite journal|journal=Science |month=May|year= 1983|volume= 220|issue=4597|pages=568–575|doi=10.1126/science.6301011|title=Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation|author=Samuelsson B |url=http://www.sciencemag.org/cgi/content/abstract/sci;220/4597/568|pmid=6301011] Blocking leukotriene receptors can play a role in the management of inflammatory diseases such as asthma(by the drugs montelukastand zafirlukast), psoriasis, and rheumatoid arthritis.
slow reacting substance of anaphylaxiscomprises the cysteinyl leukotrienes. These have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in atherosclerosisand inflammatory gastrointestinal diseases.cite journal |author=Capra V |title=Molecular and functional aspects of human cysteinyl leukotriene receptors |journal=Pharmacol Res |volume=50 |issue=1 |pages=1–11 |year=2004 |pmid=15082024 |doi=10.1016/j.phrs.2003.12.012] They are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucussecretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in immediate hypersensitivity reactions.Along with PGD, they function in effector celltrafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.cite journal |author=Boyce J |title=Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications |journal=Chem Immunol Allergy |volume=87 |issue= |pages=59–79 |year=2005 |pmid=16107763 |doi=10.1159/000087571]
In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized
prostaglandinas a component of semen. Between 1929 and 1932, Burr and Burr showed that restricting fat from animal's diets led to a deficiency disease, and first described the essential fatty acids.cite journal
author=Burr, G.O. and 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|format=PDF] In 1935, von Euler identified prostaglandin.In 1964, Bergström and Samuelsson linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids.cite journal
author=Bergström, S., Danielsson, H. and Samuelsson, B.
journal= Biochim. Biophys. Acta |volume=90 |issue=207 |year=1964
title=The enzymatic formation of prostaglandin E2 from arachidonic acid
pmid=14201168] In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.cite journal
author=Vane, J. R. | pages=232–5 | pmid=5284360
year = 1971 | month= June | day= 23
title= Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs
journal=Nature New Biol. |volume= 231 |issue=25 ] Von Euler received the
Nobel Prizein medicine in 1970, whichSamuelsson, Vane, and Bergström also received in 1982.
E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.
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Look at other dictionaries:
eicosanoid — noun Etymology: eicosa containing 20 atoms (from Greek eikosa twenty, from eikosi) + noic, suffix used in names of fatty acids (from ane + oic) + 1 oid more at vigesimal Date: 1980 any of a class of compounds (as the prostaglandins) derived from… … New Collegiate Dictionary
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