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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.
- See related detail at Essential Fatty Acid Interactions—Nomenclature
- 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),
- One A-B-C sequence-letter; and
- A subscript, indicating the number of double bonds.
- 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.
- Lipoxygenase, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes.
|'Classical' eicosanoids||Other signaling molecules derived from 20-carbon essential fatty acids|
|The free fatty acid has two
possible eicosanoid fates:
| Other oxygenation pathways make
|There is also ethanolamide or glycerol|
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.
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.
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. 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. (See diagram at PPAR).
|File:Prostaglandin E1.svg||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 three conjugated double bonds.|
|File:Prostaglandin I2.png||File:Leukotriene E4.svg|
|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|
|PGE2|| Smooth muscle contraction;
inducing pain, heat, fever;
|PGF2α||Uterine contraction||LTB4||Leukocyte chemotaxis|
|PGI2||Inhibition of platelet aggregation;
vasodilation; embryo implantation
|Cysteinyl-LTs|| Anaphylaxis; bronchial smooth|
|†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. Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors.
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
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. 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.
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. File:EFA to Eicosanoids.svg
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. 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. 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.
- 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. Likewise, EPA inhibits the production of series-2 PG and TX. Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs. EPA lowers the formation of the AA-derived cysteinyl leukotrienes (series-4 LTC, LTD, LTE) forming the much less active series-5 instead. Another ω-3 fat, DHA (22:5 ω-3), does not form eicosanoids but inhibits the formation of AA-derived prostanoids.
- Counteraction—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2. It also yields the leukotriene LTB5 which impedes the action of the AA-derived LTB4.
Complexity of pathways
|“||The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with.||”|
—Daniele Piomelli, Arachidonic Acid
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. 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|
|Bimatoprost||PG analog||Glaucoma, ocular hypertension|
|Carboprost||PG analog|| Labor induction, abortifacient|
in early pregnancy
|Iloprost||PGI2 analog||Pulmonary arterial hypertension|
|Latanoprost||PG analog||Glaucoma, ocular hypertension|
|Misoprostol||PGE1 analog|| Stomach ulcers, labor induction, |
|Montelukast|| LT receptor
|Asthma, seasonal allergies|
|Travoprost||PG analog||Glaucoma, ocular hypertension|
|Treprostinil||PGI analog||Pulmonary hypertension|
|U46619|| Longer lived
|Zafirlukast|| LT receptor
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
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.
Action of leukotrienes
- Main article: Leukotriene
Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion. LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. 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. 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.
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. 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. In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis. 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.
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