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Eicosanoid synthesis

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

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.[1][2][3][4]

NomenclatureEdit

See related detail at Essential Fatty Acid Interactions—Nomenclature

"Eicosanoid" (eicosa-, Greek for "twenty"; see icosahedron) is the collective term[5] for oxygenated derivatives of three different 20-carbon essential fatty acids:

Current usage limits the term to the leukotrienes (LT) and three types of prostanoidsprostaglandins (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'[6][7][8] in contrast to the 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'.[9][10][11][12]

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

  • Its two letter abbreviation (above),[13]
  • One A-B-C sequence-letter;[14] 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).

BiosynthesisEdit

Main article: Eicosanoid 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 speciesEdit

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.[15][16]

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,[2] (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.[4]

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.

Structures of Selected Eicosanoids
Prostaglandin E1 170px File:Leukotriene B4.svg
Prostaglandin E1. The 5-member ring is characteristic of the class. Thromboxane A2. Oxygens
have moved into the ring.
Leukotriene B4. Note the 3 conjugated double bonds.
200px 200px
Prostacyclin I2. The second ring distinguishes it from the prostaglandins. Leukotriene E4, an example of a cysteinyl leukotriene.

Prostanoid pathwaysEdit

Main article: Prostanoid#biosynthesis
Several drugs lower inflammation by blocking prostanoid synthesis; see detail at Cyclooxygenase, Aspirin and NSAID.

Cyclooxygenase (COX) comes in at least three isoforms, COX-1, -2, -3.[17] COX-1 is responsible for basal prostaglandin synthesis, while COX-2 is important in inflammatory and "induced" settings.[2] COX-3 is active in nervous tissue.[3] COX catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process. First, two molecules of O2 are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more detail of these steps at Cyclooxygenase).

All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings.

Leukotriene pathways Edit

Main article: Leukotriene#synthesis

The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD4. The leukotriene LTD4 is then cleaved by dipeptidases to make LTE4. The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively known as the cysteinyl leukotrienes.

Function and pharmacologyEdit

Metabolic actions of selected prostanoids and leukotrienes[18]
PGD2 Promotion of sleep TXA2 Stimulation of platelet
aggregation; vasoconstriction
PGE2 Smooth muscle contraction;
inducing pain, heat, fever;
bronchoconstriction
15d-PGJ2 Adipocyte differentiation
PGF Uterine contraction LTB4 Leukocyte chemotaxis
PGI2 Inhibition of platelet aggregation;
vasodilation; embryo implantation
Cysteinyl-LTs Anaphylaxis; bronchial smooth
muscle contraction.
Shown eicosanoids are AA-derived; EPA-derived generally have weaker activity

Eicosanoids exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. They are found in most living things. In humans, eicosanoids are local hormones that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated.

Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes.[19] Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors.

Receptors: There are specific receptors for all eicosanoids (see also: eicosanoid receptors)
Leukotrienes:
  • CysLT1 (Cysteinyl leukotriene
    receptor type 1)
  • CysLT2 (Cysteinyl leukotriene
    receptor type 2)
  • BLT1 (Leukotriene B4 receptor)
Prostanoids:
  • PGD2: DP-(PGD2)
  • PGE2:
    • EP1-(PGE2)
    • EP2-(PGE2)
    • EP3-(PGE2)
    • EP4-(PGE2)
  • PGF: FP-(PGF)
  • PGI2 (prostacyclin): IP-(PGI2)
  • TXA2 (thromboxane): TP-(TXA2)

The ω-3 and ω-6 series Edit

Main article: Essential fatty acid interactions
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.

—Kevin Fritsche, Fatty Acids as Modulators of the Immune Response[20]

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.[3]

In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3) provides the most important competing cascade. DGLA (20:3 ω-6) provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory 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.[21]

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.[20] Of these, the action on eicosanoids is the best explored.

Mechanisms of ω-3 actionEdit

File:EFA to Eicosanoids.svg

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 Edit

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.

Pharmacy: Eicosanoid, eicosanoid analogs and receptor agonists/antagonists used as medicines
Medicine Type Medical condition or use
Alprostadil PGI1 Erectile dysfunction, maintaining a
patent ductus arteriosus in the fetus
Beraprost PGI1 analog Pulmonary hypertension, avoiding
reperfusion injury
Bimatoprost PG analog Glaucoma, ocular hypertension
Carboprost PG analog Labor induction, abortifacient
in early pregnancy
Dinoprostone PGE2 Labor induction
Iloprost PGI2 analog Pulmonary arterial hypertension
Latanoprost PG analog Glaucoma, ocular hypertension
Misoprostol PGE1 analog Stomach ulcers, labor induction,
abortifacient
Montelukast LT receptor
antagonist
Asthma, seasonal allergies
Travoprost PG analog Glaucoma, ocular hypertension
Treprostinil PGI analog Pulmonary hypertension
U46619 Longer lived
TX analog
Research only
Zafirlukast LT receptor
antagonist
Asthma

Action of prostanoidsEdit

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 PPARγ members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription.[22]

Action of leukotrienesEdit

Main article: Leukotriene

Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion.[23] LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils.[24] 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.[25] 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.[24] Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.[26]

HistoryEdit

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.[27] 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.[28] In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.[29] Von Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and Bergström also received in 1982. E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.

ReferencesEdit

  1. DeCaterina, R and Basta, G (June 2001). n-3 Fatty acids and the inflammatory response – biological background. European Heart Journal Supplements 3, Suppl D: D42–D49.
  2. 2.0 2.1 2.2 Funk, Colin D. (30 November 2001). Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology. Science 294 (5548): 1871–1875.
  3. 3.0 3.1 3.2 Piomelli, Daniele (2000). Arachidonic Acid.
  4. 4.0 4.1 Soberman, Roy J. and Christmas, Peter (2003). The organization and consequences of eicosanoid signaling. J. Clin. Invest 111: 1107–1113.
  5. Beare-Rogers (2001). IUPAC Lexicon of Lipid Nutrition. (PDF)
  6. Van Dyke TE, Serhan CN (2003). Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J. Dent. Res. 82 (2): 82–90.
  7. Serhan CN, Gotlinger K, Hong S, Arita M (2004). Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat. 73 (3-4): 155–72.
  8. Anderle P, Farmer P, Berger A, Roberts MA (2004). Nutrigenomic approach to understanding the mechanisms by which dietary long-chain fatty acids induce gene signals and control mechanisms involved in carcinogenesis. Nutrition (Burbank, Los Angeles County, Calif.) 20 (1): 103–8.
  9. Evans AR, Junger H, Southall MD, et al (2000). Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons. J. Pharmacol. Exp. Ther. 293 (3): 912–20.
  10. O'Brien WF, Krammer J, O'Leary TD, Mastrogiannis DS (1993). The effect of acetaminophen on prostacyclin production in pregnant women. Am. J. Obstet. Gynecol. 168 (4): 1164–9.
  11. Behrendt H, Kasche A, Ebner von Eschenbach C, Risse U, Huss-Marp J, Ring J (2001). Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization. Int. Arch. Allergy Immunol. 124 (1-3): 121–5.
  12. Sarau HM, Foley JJ, Schmidt DB, et al (1999). In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity. Prostaglandins Leukot. Essent. Fatty Acids 61 (1): 55–64.
  13. Prostacyclin—PGI—was previously classified as prostaglandin and retains its old identifier.
  14. 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 Cyberlipid Center. Prostanoids. URL accessed on 2007-02-05.
  15. Cyrus, Tillmann (June 1999). Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice. J Clin Invest 103: 1597–1604n.
  16. Schewe T. (2002 Mar-Apr). 15-lipoxygenase-1: a prooxidant enzyme. Biol Chem. 383 (3-4).
  17. Warner, Timothy D. and Mitchell, Jane A. (October 8, 2002). Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?. PNAS 99 (21): 13371–13373.
  18. University of Kansas Medical Center (2004). Eicosanoids and Inflammation. (PDF) URL accessed on 2007-01-05.
  19. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. (1995 March 31). The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta. 235 (2): 207–19.
  20. 20.0 20.1 Fritsche, Kevin (August 2006). Fatty Acids as Modulators of the Immune Response. Annual Review of Nutrition 26: 45–73.
  21. National Institute of Health. Omega-3 fatty acids, fish oil, alpha-linolenic acid.
  22. Bos C, Richel D, Ritsema T, Peppelenbosch M, Versteeg H (2004). Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol 36 (7): 1187–205.
  23. Samuelsson, SE Dahlen, JA Lindgren, CA Rouzer, and CN Serhan (09-04 1987). Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237: 1171–1176.
  24. 24.0 24.1 Samuelsson B (May 1983). Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220 (4597): 568–575.
  25. Capra V (2004). Molecular and functional aspects of human cysteinyl leukotriene receptors. Pharmacol Res 50 (1): 1–11.
  26. Boyce J (2005). Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications. Chem Immunol Allergy 87: 59–79.
  27. Burr, G.O. and Burr, M.M. (1930). On the nature and role of the fatty acids essential in nutrition. J. Biol. Chem. 86 (587).
  28. Bergström, S., Danielsson, H. and Samuelsson, B. (1964). The enzymatic formation of prostaglandin E2 from arachidonic acid. Biochim. Biophys. Acta 90 (207).
  29. Vane, J. R. (June 1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 231 (25): 232–5.

External linksEdit

Template:Lipids Template:Autacoids Template:Eicosanoids


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