Eicosanoid
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Overview
In biochemistry, eicosanoids are signaling molecules derived from omega-3 (ω-3) or omega-6 (ω-6) fats. They exert complex control over many bodily systems, especially in inflammation, 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.
The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts 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 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 essential fatty acid. These series' different activities largely explain the health effects of ω-3 and ω-6 fats.[1][2][3][4]
Nomenclature
- 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:
- 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, epoxyeicosatrienoic acids (EETs) and some endocannabinoids.
A particular eicosanoid is denoted by a four-character abbreviation, composed of:
- Its two letter abbreviation (above),[6]
- One A-B-C sequence-letter;[7] 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).
Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids:
- Cyclooxygenase, or COX, which comes in at least three isoforms, COX-1, -2, -3 – leading to the prostanoids.[8]
- Lipoxygenase, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes.
Biosynthesis
| 'Classical' eicosanoids | Other signaling molecules derived from 20-carbon essential fatty acids | |
|---|---|---|
| The free fatty acid has two possible eicosanoid fates:
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Other oxygenation pathways make related products:
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There is also ethanolamide or glycerol addition:
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Eicosanoids are a class of oxygenated fatty acids, found widely in a variety of microorganisms, plants and animals. 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. They are potent in the nanomolar range. Eicosanoids are not stored within cells, but are synthesized as required. They derive from fatty acids which are incorporated as esters into larger molecules—the phospholipids and diacylglycerols—found in the cell membrane and nuclear membrane.
The first step of eicosanoid biosynthesis occurs 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.) This triggers the release of a phospholipase at the cell wall. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C). This frees a 20-carbon essential fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation.
The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A2 (cPLA2) is the key actor, as cells lacking cPLA2 are generally devoid of eicosanoid synthesis. The phospholipase cPLA2 is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.[9]
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 COX) add molecular oxygen (O2). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity.
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 isoforms.[4]
Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.[10][11] The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes which are biosynthetic for eicosanoids (e.g. glutathione-S-transferases, epoxide hydrolases and carrier proteins) belong to families whose functions are largely involved with cellular detoxification. This suggests that eicosanoid signaling may 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 DNA-transcription there; LTB4 is ligand for PPARα.[2] (See diagram at PPAR).
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| Prostaglandin E1. The 5-member ring is characteristic of the class. | Thromboxane A2. Oxygens have moved into the ring. | Leukotriene B4. Note the three conjugated double bonds. | |
| File:Prostaglandin I2.png | Error creating thumbnail: File missing | ||
| Prostacyclin I2. The second ring distinguishes it from the prostaglandins. | Leukotriene E4, an example of a cysteinyl leukotriene. | ||
Biosynthesis of prostanoids
- Several drugs lower inflammation by blocking prostanoid synthesis; see detail at Cyclooxygenase, Aspirin and NSAID.
Cyclooxygenase (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. (See more detail, including the enzymes involved, in diagrams at Prostanoid.)
Biosynthesis of leukotrienes
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 pharmacology
| PGD2 | Promotion of sleep | TXA2 | Stimulation of platelet aggregation; vasoconstriction |
| PGE2 | Smooth muscle contraction; inducing pain, heat, fever; bronchoconstriction |
15d-PGJ2 | Adipocyte differentiation |
| PGF2α | 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 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.[12] Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors.
Leukotrienes:
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Prostanoids:
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The ω-3 and ω-6 series
| “ | 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[13] | ||
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.[14]
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.[13] 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. Animal studies show that increased dietary ω-3 results in decreased AA in brain and other tissue.[15] Linolenic acid (18:3 ω-3) contributes to this by displacing linoleic acid (18:2 ω-6) from the elongase and desaturase enzymes that produce AA. EPA inhibits phospholipase A2's release of AA from cell membrane.[16] Other mechanisms involving the transport of EFAs may also play a role. The reverse is also true – high dietary linoleic acid decreases the body's conversion of α-linolenic acid to EPA. However, the effect is not as strong; the desaturase has a higher affinity for α-linolenic acid than it has for linoleic acid.[17]
- 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. For example, dietary GLA increases tissue DGLA and lowers TXB2.[18][19] Likewise, EPA inhibits the production of series-2 PG and TX.[20] Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs.[21] EPA lowers the formation of the AA-derived cysteinyl leukotrienes (series-4 LTC, LTD, LTE) forming the much less active series-5 instead.[22] Another ω-3 fat, DHA (22:5 ω-3), does not form eicosanoids but inhibits the formation of AA-derived prostanoids.[23]
- Counteraction—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2.[24] It also yields the leukotriene LTB5 which impedes the action of the AA-derived LTB4.[25]
Complexity of pathways
| “ | The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with. | ” |
—Daniele Piomelli, Arachidonic Acid[3] | ||
Eicosanoid signaling paths are complex. It is therefore difficult to characterize the action of any particular eicosanoid. For example, PGE2 binds four receptors, dubbed EP1–4. Each is coded by a separate gene, and some exist in multiple isoforms. Each EP receptor in turn couples to a G protein. The EP2, EP4 and one isoform of the EP3 receptors couple to Gs. This increases intracellular cAMP and is anti-inflammatory. EP1 and other EP3 isoforms couple to Gq. This leads to increased intracellular calcium and is pro-inflammatory. Finally, yet another EP3 isoform couples to Gi, which both decreases cAMP and increases calcium. Many immune-system cells express multiple receptors that couple these apparently opposing pathways.[26] Presumably, EPA-derived PGE3 has a somewhat different effect of on this system, but it is not well-characterized.
Role in inflammation
| 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 |
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—PGI2 and 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 a also 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 play pivotal functions inflammation, platelet aggregation, and vasoconstriction/relaxation. Prostanoids activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription.[27]
Action of leukotrienes
- Main article: Leukotriene
Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion.[28] LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils.[29] 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.[30] 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.[29] Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.[31]
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.[32] 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.[33] In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.[34] 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.
References
- ↑ DeCaterina, R and Basta, G (June, 2001). "n-3 Fatty acids and the inflammatory response – biological background" (PDF). European Heart Journal Supplements. 3, Suppl D: D42–D49. Retrieved 2006-02-10. Check date values in:
|year=(help) - ↑ 2.0 2.1 Funk, Colin D. (30 November 2001). "Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology". Science. 294 (5548): 1871–1875. doi:10.1126/science.294.5548.1871. Retrieved 2007-01-08.
- ↑ 3.0 3.1 3.2 Piomelli, Daniele (2000). "Arachidonic Acid". Neuropsychopharmacology: The Fifth Generation of Progress. Retrieved 2006-03-03.
- ↑ 4.0 4.1 Soberman, Roy J. and Christmas, Peter (2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest. 111: 1107–1113. doi:doi:10.1172/JCI200318338 Check
|doi=value (help). Retrieved 2007-01-05. - ↑ Beare-Rogers (2001). "IUPAC Lexicon of Lipid Nutrition" (PDF). Retrieved June 1. Unknown parameter
|accessyear=ignored (|access-date=suggested) (help); Check date values in:|accessdate=(help) - ↑ Prostacyclin—PGI—was previously classified as prostaglandin and retains its old identifier.
- ↑ 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". Retrieved 2007-02-05.
- ↑ 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. doi:10.1073/pnas.222543099. Retrieved 2007-01-05.
- ↑ 9.0 9.1 University of Kansas Medical Center (2004). "Eicosanoids and Inflammation" (PDF). Retrieved 2007-01-05.
- ↑ Cyrus, Tillmann (June 1999). "Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice". J Clin Invest. 103 (11): 1597–1604n.
- ↑ Schewe T. (2002 Mar-Apr). "15-lipoxygenase-1: a prooxidant enzyme". Biol Chem. 383 (3–4). Retrieved 2007-01-09. Text "pages: 365-74
" ignored (help); Check date values in:
|year=(help) - ↑ Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. (1995 Mar 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. PMID 7554275. Check date values in:
|year=(help);|access-date=requires|url=(help) - ↑ 13.0 13.1 Fritsche, Kevin (August 2006). "Fatty Acids as Modulators of the Immune Response". Annual Review of Nutrition. 26: 45–73. doi:doi:10.1146/annurev.nutr.25.050304.092610 Check
|doi=value (help). Retrieved 2007-01-11. - ↑ National Institute of Health (August 1, 2005). "Omega-3 fatty acids, fish oil, alpha-linolenic acid". Retrieved March 26. Unknown parameter
|accessyear=ignored (|access-date=suggested) (help); Check date values in:|accessdate=(help) - ↑ Medical Study News (25-May-2005). "Brain fatty acid levels linked to depression". Retrieved February 10. Unknown parameter
|accessyear=ignored (|access-date=suggested) (help); Check date values in:|accessdate=, |year=(help)- Who were in turn citing Pnina Green, Iris Gispan-Herman and Gal Yadid (June 2005). "Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression". Retrieved 2006-02-10.
- ↑ KP Su, SY Huang, CC Chiu, WW Shen (2003). "Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled ..." (PDF). Retrieved 2006-02-22.
- ↑ Phinney, SD , RS Odin, SB Johnson and RT Holman (1990). "Reduced arachidonate in serum phospholipids and cholesteryl esters associated with vegetarian diets in humans". American Journal of Clinical Nutrition. 51: 385–392. Retrieved 2006-02-11.
- "[D]ietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction."
- ↑ Guivernau M, Meza N, Barja P, Roman O. (Nov 1994). "Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production.". PMID 7846101.
|access-date=requires|url=(help)- GLA decreases triglycerides, LDL, increases HDL, decreases TXB2 and other inflammatory markers. Review article; human and rat studies.
- ↑ Karlstad MD, DeMichele SJ, Leathem WD, Peterson MB. (Nov 1993). "Effect of intravenous lipid emulsions enriched with gamma-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after burn and endotoxin injury in rats". PMID 8222692. Unknown parameter
|accessyear=ignored (|access-date=suggested) (help); Check date values in:|accessdate=(help);|access-date=requires|url=(help)- IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB2.
- ↑ Calder, Philip C. (September 2004). "n-3 Fatty Acids and Inflammation – New Twists in an Old Tale". Retrieved February 8. Unknown parameter
|accessyear=ignored (|access-date=suggested) (help); Check date values in:|accessdate=(help)- Invited review article, PUFA Newsletter.
- ↑ Belch, Jill JF and Alexander Hill (January 2000). "Evening primrose oil and borage oil in rheumatologic conditions". Retrieved 2006-02-12.
- "DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation."
- ↑ Lee TH, Mencia-Huerta JM, Shih C, Corey EJ, Lewis RA, Austen KF (1984). "Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils". : J Clin Invest. 74 (6): 1922-33. PMID 6096400. Retrieved 2007-01-31. Unknown parameter
|month=ignored (help) - ↑ Corey E, Shih C, Cashman J (1983). "Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis" (PDF). Proc Natl Acad Sci U S A. 80 (12): 3581–4. PMID 6304720.
- ↑ Fan, Yang-Yi and Robert S. Chapkin (9 September 1998). "Importance of Dietary gamma -Linolenic Acid in Human Health and Nutrition". Journal of Nutrition. 128 (9): 1411–1414. Retrieved 2007-01-05.
- "[D]ietary GLA increases the content of its elongase product, dihomo-gamma linolenic acid (DGLA), within cell membranes without concomitant changes in arachidonic acid (AA). Subsequently, upon stimulation, DGLA can be converted by inflammatory cells to 15-(S)-hydroxy-8,11,13-eicosatrienoic acid and prostaglandin E1. This is noteworthy because these compounds possess both anti-inflammatory and antiproliferative properties."
- ↑ Prescott S (1984). "The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils" (PDF). J Biol Chem. 259 (12): 7615–21. PMID 6330066. Retrieved 2006-02-12.
- ↑ Tilley S, Coffman T, Koller B (2001). "Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes". J Clin Invest. 108 (1): 15–23. PMID 11435451. Retrieved 2007-01-30.
- ↑ 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. PMID 15109566.
- ↑ Samuelsson, SE Dahlen, JA Lindgren, CA Rouzer, and CN Serhan (1987). "Leukotrienes and lipoxins: structures, biosynthesis, and biological effects". Science. 237 (4819): 1171–1176. doi:10.1126/science.2820055. Retrieved 2007-01-22. Unknown parameter
|month=ignored (help) - ↑ 29.0 29.1 Samuelsson B (1983). "Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation". Science. 220 (4597): 568–575. doi:10.1126/science.6301011. Unknown parameter
|month=ignored (help) - ↑ Capra V (2004). "Molecular and functional aspects of human cysteinyl leukotriene receptors". Pharmacol Res. 50 (1): 1–11. PMID 15082024.
- ↑ Boyce J (2005). "Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications". Chem Immunol Allergy. 87: 59–79. PMID 16107763.
- ↑ Burr, G.O. and Burr, M.M. (1930). "On the nature and role of the fatty acids essential in nutrition" (PDF). J. Biol. Chem. 86 (587). Retrieved 2007-01-17.
- ↑ Bergström, S., Danielsson, H. and Samuelsson, B. (1964). "The enzymatic formation of prostaglandin E2 from arachidonic acid". Biochim. Biophys. Acta. 90 (207). PMID 14201168.
- ↑ Vane, J. R. (1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs". Nature New Biol. 231 (25): 232–5. PMID 5284360. Unknown parameter
|month=ignored (help); Unknown parameter|day=ignored (help)
External links
- Eicosanoids at the US National Library of Medicine Medical Subject Headings (MeSH)