Eicosanoid

In biochemistry, eicosanoids are signaling molecules made by oxygenation of twenty-carbon essential fatty acids, (EFAs).They exert complex control over many bodily systems, mainly in inflammation or 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 aspirin and 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
pages=D42–D49
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
url= http://www.sciencemag.org/cgi/content/full/294/5548/1871
pmid= 11729303] cite journal|author=Piomelli, Daniele |title=Arachidonic Acid
url= http://www.acnp.org/g4/GN401000059/Default.htm
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]

Nomenclature

:"See related detail at Essential Fatty Acid Interactions—Nomenclature"Eicosanoid" ("eicosa-", Greek for "twenty"; "see icosahedron") is the collective termcite web
author=Beare-Rogers
title=IUPAC Lexicon of Lipid Nutrition
year=2001
url=http://www.iupac.org/publications/pac/2001/pdf/7304x0685.pdf
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).

Furthermore, stereochemistry may differ among the pathways, indicated by Greek letters, e.g. for (PGF_2α).

Biosynthesis

Two families of enzymes catalyze 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.

Eicosanoids are not stored within cells, but are synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane.

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.) Phospholipase is released at the cell membrane and travels to the nuclear membrane.There, it frees 20-carbon essential fatty acids. This event appears to be the rate-determining step for 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" Lipoxygenase or 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 pathogenesis of atherosclerosis.cite journal
author=Cyrus, Tillmann
journal= J Clin Invest
url= http://www.jci.org/cgi/content/abstract/103/11/1597
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
accessdate= 2007-01-09
unused_data=|pages: 365-74]

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 ligand for 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
author=Fritsche, Kevin
journal= Annual Review of Nutrition
volume= 26 |pages=45–73 |month= August | year= 2006
doi= 10.1146/annurev.nutr.25.050304.092610
title= Fatty Acids as Modulators of the Immune Response
url= http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.nutr.25.050304.092610?journalCode=nutr
accessdate= 2007-01-11]
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 mental illnesses.

The U.S. National Institutes of Health and the National Library of Medicine state that there is 'A' level evidence ('strong scientific evidence') that increased dietary ω-3 improves outcomes in hypertriglyceridemia, secondary cardiovascular disease prevention and hypertension.There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in primary prevention of cardiovascular disease, rheumatoid arthritis and protection from ciclosporin toxicity in organ transplant patients.They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.cite web
author=National Institute of Health
url= http://www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-fishoil.html
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 cytokine biosynthesis 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 vasodilators PGE₂ and LTB₄. The blood vessels engorge and the injury reddens.
"Swelling"—LTB₄ makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also 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

:"Main articles: Prostaglandin, Prostacyclin and Thromboxane"Prostanoids mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain and 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 PPAR_γ 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 hormone secretion.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 chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in 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 montelukast and zafirlukast), psoriasis, and rheumatoid arthritis.

The slow reacting substance of anaphylaxis comprises 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 atherosclerosis and 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 mucus secretion. 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 cell trafficking, 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]

History

In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized prostaglandin as 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
url=http://www.jbc.org/cgi/reprint/97/1/1.pdf |accessdate=2007-01-17
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 Prize in 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.

References

External links

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