In biochemistry, eicosanoids are signaling molecules made by oxidation of 20-carbon fatty acids. They exert complex control over many bodily systems; mainly in growth during and after physical activity, inflammation or immunity after the intake of toxic compounds and pathogens, and as messengers in the central nervous system. Many are classified as hormone-like autocrine (i.e. acting on their cells of origin) and paracrine (i.e. acting on cells close to their cells of origin) Cell signaling agents. The networks of controls that depend upon eicosanoids are among the most complex in the human body.
Eicosanoids are formed primarily from two classes of polyunsaturated fatty acids viz., omega-6 (ω-6) and omega-3 (ω-3) fatty acids. Since humans as well as other mammals are unable to convert omega-6 to omega-3 fatty acids, the relative levels of the two classes in mammalian tissues and, consequently, the relative amounts of the ω-6 fatty acid-derived versus ω-3 fatty acid-derived eicosanoids that these tissues make is directly dependent on the relative amounts of dietary ω-6 versus ω-6 fatty acids consumed (see omega 3 fatty acids.). These points are important because eicosanoids derived from the two fatty acid classes often have opposing actions. For example, many of the ω-6 fatty acid-derived eicosanoids possess pro-inflammatory activity while those derived from ω-3 fatty acids possess weaker or no pro-inflammatory activity; in these cases the ω-3 fatty acids compete with ω-6 fatty acids for the same metabolic pathways thereby replacing the production of ω-6 fatty acid-derived active products with relatively inactive ω-3 fatty acid-derived products (see specialized pro-resolving mediators). Furthermore, certain of the ω-3 fatty acid-derived eicosanoids, termed resolvins (as well as metabolites [termed docosanoids] of the ω-3 fatty acid, docosahexaenoic acid, have potent anti-inflammatory activity (seespecialized pro-resolving mediators#SPM and inflammation. Likewise, ω-6 fatty acid-derived eicosanoids promote while ω-3 fatty acid-derived eicosanoids dampen allergy reactions, atherosclerosis, high blood pressure, cancer cell growth, and other physiological as well as pathological processes. Thus, ω-6 fatty acid-rich diets are proposed to promote and ω-3 fatty acid-rich diets are proposed to suppress not only inflammation but also allergy reactions, atherosclerosis, hypertension, cancer growth, and ther processes.
There are multiple subfamilies of eicosanoids, including the prostaglandins, thromboxanes, and leukotrienes, as well as the lipoxins, resolvins and eoxins, and others as noted in the following Nomenclature section. For each, there are two or three separate series, derived from either an ω-3 or an ω-6 EFA. These series' different activities largely explain the health effects of ω-3 and ω-6 fats.
- 1 Nomenclature
- 2 Biosyntheses
- 3 Function and pharmacology
- 4 History
- 5 References
- 6 External links
- See related detail at Essential Fatty Acid Interactions—Nomenclature
Fatty Acid Sources
- Arachidonic acid (AA), an ω-6 fatty acid, with 4 double bonds;
- Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds;
- Dihomo-gamma-linolenic acid (DGLA), an ω-6 fatty acid, with 3 double bonds.
In addition, one fatty acid, mead acid (i.e. Z,8Z,11Z-eicosatrienoic acid), is an ω-9 fatty acid containing 3 double bonds; it is metabolized to a very limited number of eicosanoids.
A particular eicosanoid is denoted by a four-character abbreviation, composed of:
- its two-letter abbreviation (LT, EX or PG, as described above),
- one A-B-C sequence-letter,
- 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 (PGF2α).
Current usage limits the term eicosanoid to:
- ω-6 Series eicosanoids:
- Hydroxyeicosatetraenoic acids (HETE) include the following metabolites of arachidonic acid:
- Leukotrienes (LT) include the following metabolites of arachidonic acid:
- Eoxins (EX) include the following metabolites of arachidnoic acid:
- Prostanoids consisting of three different types:
- Prostaglandins (PG) include the following metabolites of arachidonic acid:
- Prostacyclins, a subset of the PGs which includes only one arachidonic acid metabolite, PGI2 (see prostacyclin).
- Thromboxanes (TX) include the following metabolites of aracidonic acid:
- Resolvins of the E series (RvE) (D series resolvins (RvD's are metabolites of the 22-carbon ω-6 fatty acid docosahexaenoic acid; see Specialized pro-resolving mediators#DHA-derived Resolvins) include the following metabolites of eicosapentaenoic acid:
- RvE1, 18S-RvE1, RvE2, and RvE3 (see Specialized pro-resolving mediators#Resolvins).
- Other ω-3 Series eicosapentaenoic acid products are analogs of ω-6 fatty acid-derived metabolites but contain a double bond between carbon 17 and 18 and therefore have one more double bound than their arachidonic acid-derived analogs. They include:
- 5-HEPE (see Arachidonate 5-lipoxygenase#Eicosapentaenoic acid), 12-HEPE, 15-HEPE, and 20-HETE; LTA5, LTB5 (see Essential fatty acid interactions#counteractions, LTC5, LTD5, and LTE5 (see Arachidonate 5-lipoxygenase#eicosapentaenoic acid); PGE3, PGD3, PGF3α, and Δ(17)-6-keto PGF1α; PGI3 (see Essential fatty acid interactions#counteraction); and TXA3 and TXB3 (see Essential fatty acid interactions#nomenclature).
- ω-3 Series eicosanoids derived from dihomo-gamma-linolenic acid are analogs of arachidonic acid-derived eicosanoids but lack a double bound between carbons 5 and 6 and therefore have 1 less double bound than their arachidonic acid-derived analogs; these metabolites include:
- PGA1, PGE1, and TXA1 (see dihomo-gamma-linolenic acid).
- The ω-9 fatty acid, mead acid, is metabolized to the 3 double bond-containing analog of 5-HETE viz., 5-HETrE (see arachidonate 5-lipoxygenase#mead acid).
However, several other classes can technically be termed eicosanoid, including:
- Oxoeicosanoids (oxo-ETE) include the following metabolites:
- Hepoxilins (Hx) include the following arachidonic acid metabolites:
- HxA3 and HxB3 (see Hepoxilins).
- Lipoxins (LX) include the following metabolites of arachidonic acid:
- LxA4 and LxB4(see Specialized pro-resolving mediators).
- Epi-lipoxins (epi-Lx) include the following metabolites of arachidonic acid:
- 15-epi-LxA4 (also termed AT-LxA4) and 15-epi-LxB4 (also termed AT-LxB4)(see Specialized pro-resolving mediators).
- Epoxyeicosatrienoic acids (EET) include the following metabolites of arachidonic acid:
- 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET (see epoxyeicosatrienoic acid).
- Epoxyeicosatetraenoic acid (EEQ) include the following metabolites of eicosapentaenoic acid:
- 5,6-EEQ, 8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 15,16-EEQ (see epoxyeicosatetraenoic acid).
- Isoprostanes (isoP) are non-enzymatically formed derivatives of polyunsaturated fatty acids studied as markers of oxidative stress; they include the following arachidonic acid-derived classes named based on their structural similarities to PGs:
- D2-isoPs, E2-isoPs, A2-isoPs, and J2-isoPs; two isoPs, 5,6-epoxyisoprostane E2 and 5,6-epoxyisoprostane A2, have been shown to possess anti-inflammatory (see Specialized pro-resolving mediators#Prostaglandins and Isoprostanes).
- Isofurans are non-enzymatically formed dervatives of polyunsaturated fatty acids that possess a Furan ring structure; they are studied as markers of oxidative stress. There are 256 potentially different furan ring-containing isomers that can be derived from arachidonic acid.
- Endocannabinoids are certain glycerolipids or dopmamine that are esterified to polyunsaturated fatty acids that activate cannabinoid receptors. They include the following arachidonic acid-esterified agents:
Synthesis of the eicosapentaenoic acid-derived HEPEs, leukotrienes, prostanoids, epoxyeicosatetraenoic acids; the dihomo-gamma-linolenic acid-derived prostanoids; and mead acid-derived 5-HEPE and 5-oxo-EPE involve the same pathways that make their arachidonic acid-derived analogs.
Eicosanoids typically are not stored within cells but rather synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane. These fatty acids must be released from their membrane sites and then metabolized initially to products which most often are further metabolized through various pathways to make the large array of products we recognize as bioactive eicosanoids.
Fatty acid mobilization
Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma, ischemia, other physical perturbations, attack by pathogens, or stimuli made by nearby cells, tissues, or pathogens such as chemotactic factors, cytokines, growth factors, and even certain eicosanoids. The activated cells then mobilize enzymes, termed phospholipase A2's (PLA2s), capable of releasing ω-6 and ω-3 fatty acids from membrane storage. These fatty acids are bound in ester linkage to the SN2 position of membrane phospholipids; PLA2s act as esterases to release the fatty. There are several classes of PLA2s with type IV cytosolic PLA2s (cPLA2s) appearing to be responsible for releasing the fatty acids under many conditions of cell activation. The cPLA2s act specifically on phospholipids that contain AA, EPA or GPLA at their 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 oxidations proceed with high stereoselectivity (enzymatic oxidations are considered practically stereospecific).
Four families of enzymes initiate or contribute to the initiation of the catalyze of fatty acids to eicosanoids:
- Cyclooxygenases (COXs): (COX-1 or COX-2 initiate the metabolism of arachidonic acid to prostanoids.
- Lipoxygenases (LOXs): 5-Lipoxygenase (5-LOX) initiates the metabolism of arachidonic acid to 5-HETE, 5-oxo-ETE, and the leukotrienes; acts via transcellular syntheses in series with 15-lipoxygenase (15-LOX), 12-lipoxygenase (12-LOX), or aspirin-treated COX-2 to metabolize arachidonic acid to lipoxins; and acts via transcellular synthesis in series with cytochrome P450 monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series resolvins (ReVs). 15-LOX initiates the metabolizes of arachidonic acid to 15-hydroperoxy-eicosatentraeonlic acid 15-HETE and the eoxins. 12-Lipoxygenase initiates the metabolism of arachidonic acid to 12-HETE and the hepoxilins.
- Cytochrome P450 monooxygenases metabolize arachidonic acid to 20-HETE and 19-HETE
- Epoxygenases are a large number of cytochrome P450 enzymes which generate nonclassic eicosanoid epoxides derived from arachidonid acid viz., 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET.
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 that are biosynthetic for eicosanoids (e.g., glutathione-S-transferases, epoxide hydrolases, and carrier proteins) belong to families whose functions are involved largely with cellular detoxification. This suggests that eicosanoid signaling might 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).
Cyclooxygenase (COX) catalyzes the conversion of the free 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.)
Several drugs lower inflammation by blocking prostanoid synthesis; see detail at Cyclooxygenase, Aspirin and NSAID. Aspirin is especially important in resolution of inflammation because it doesn't only inhibit cyclooxygenases, but also switches COX-2 from producing pro-inflammatory prostaglandins to producing lipoxins that are mostly anti-inflammatory.
Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways
The enzyme 5-lipoxygenase (5-LO or ALOX5) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which if not further metabolized by the enzyme LTA synthase, is rapidly reduces to 5-hydroxyeicosatetraenoic acid (5-HETE) by ubiquitous cellular glutathione-dependent peroxidases. The enzyme LTA synthase acts on 5-HPETE 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.
The enzyme arachidonate 12-lipoxygenase (12-LO or ALOX12) metabolizes arachidonic acid to the S stereoisomer of 12-hydroperoxyeicosatetraenoic acid (5-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 12-hydroxyeicosatetraenoic acid (12-HETE) or further metabolized to hepoxilins (Hx) such as HxA3 and HxB.
The enzymes 15-lipoxygenase-1 (15-LO-1 or ALOX15) and 15-lipoxygenase-2 (15-LO-2, ALOX15B) metabolize arachidonic acid to the S stereoisomer of 15-Hydroperoxyeicosatetraenoic acid (15-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 15-Hydroxyicosatetraenoic acid (15-HETE).
A subset of Cytochrome P450 (CYP450) microsome-bound ω-hydroxylases (see 20-Hydroxyeicosatetraenoic acid) metabolize arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) and 19-hydroxyeicosatetraenoic acid by an omega oxidation reaction.
The human cytochrome P450 (CYP) epoxygenases, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 metabolize arachidonic acid to the non-classic Epoxyeicosatrienoic acids (EETs) by coverting one of the fatty acid's double bonds to its epoxide to form one or more of the following EETs, 14,15-ETE, 11,12-EET, 8,9-ETE, and 4,5-ETE. 14,15-EET and 11,12-EET are the major EETs produced by mammalian, including human, tissues. The same CYPs but also CYP4A1, CYP4F8, and CYP4F12 metabolize eicosapentaenoic acid to five epoxide epoxyeicosatetraenoic acids (EEQs) viz., 17,18-EEQ, 14,15-EEQ, 11,12-EEQ. 8,9-EEQ, and 5,6-EEQ (see epoxyeicosatetraenoic acid).
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; in general, EPA-derived 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. 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 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 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 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 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 loses 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.
|Medicine||Type||Medical condition or use|
|Alprostadil||PGE1||Erectile dysfunction, maintaining a
patent ductus arteriosus in the fetus
|Beraprost||PGI1 analog||Pulmonary hypertension, avoiding
|Bimatoprost||PGF2α analog||Glaucoma, ocular hypertension|
|Carboprost||PGF2α analog||Labor induction, abortifacient
in early pregnancy
|Iloprost||PGI2 analog||Pulmonary arterial hypertension|
|Latanoprost||PGF2α analog||Glaucoma, ocular hypertension|
|Misoprostol||PGE1 analog||Stomach ulcers, labor induction,
|Asthma, seasonal allergies|
|Travoprost||PGF2α analog||Glaucoma, ocular hypertension|
|Treprostinil||PGI analog||Pulmonary hypertension|
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.
Action of leukotrienes
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.
Action of epoxyeicosanoids
The Epoxy eicostrienoic acids or EETs and, it is in general presumed if not clearly shown, the epoxy eicosatetraenoic acids have vasodilating actions on heart, kidney and other blood vessels as well as on the kidney's reabsorption of sodium and water that act to reduce blood pressure and ischemic and other injuries to the heart, brain, and other tissues; they may also act to reduce inflammation, promote the growth and metastasis of certain tumors, promote the growth of new blood vessels, in the central nervous system regulate the release of neuropeptide hormones, and in the peripheral nervous system inhibit or reduce pain perception.
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.
- Edwards IJ, O'Flaherty JT (2008). "Omega-3 Fatty Acids and PPARgamma in Cancer". PPAR Research. 2008: 358052. doi:10.1155/2008/358052. PMC . PMID 18769551.
- DeCaterina, R; Basta, G (June 2001). "n-3 Fatty acids and the inflammatory response – biological background" (PDF). European Heart Journal Supplements. 3, Suppl D: D42–D49. doi:10.1016/S1520-765X(01)90118-X. Retrieved 2006-02-10.
- 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. PMID 11729303. Retrieved 2007-01-08.
- Piomelli, Daniele (2000). "Arachidonic Acid". Neuropsychopharmacology: The Fifth Generation of Progress. Retrieved 2006-03-03.
- Soberman, Roy J.; Christmas, Peter (2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest. 111 (8): 1107–1113. doi:10.1172/JCI18338. PMC . PMID 12697726. Retrieved 2007-01-05.
- Beare-Rogers (2001). "IUPAC Lexicon of Lipid Nutrition" (PDF). Retrieved June 1, 2006.
- Prostacyclin—PGI—was previously classified as prostaglandin and retains its old PGI2 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.
- Gomolka B, Siegert E, Blossey K, Schunck WH, Rothe M, Weylandt KH (2011). "Analysis of omega-3 and omega-6 fatty acid-derived lipid metabolite formation in human and mouse blood samples". Prostaglandins & Other Lipid Mediators. 94 (3-4): 81–7. doi:10.1016/j.prostaglandins.2010.12.006. PMID 21236358.
- Zulfakar MH, Edwards M, Heard CM (2007). "Is there a role for topically delivered eicosapentaenoic acid in the treatment of psoriasis?". European Journal of Dermatology : EJD. 17 (4): 284–91. doi:10.1684/ejd.2007.0201. PMID 17540633.
- Caramia G (2012). "[Essential fatty acids and lipid mediators. Endocannabinoids]". La Pediatria Medica E Chirurgica : Medical and Surgical Pediatrics (in Italian). 34 (2): 65–72. doi:10.4081/pmc.2012.2. PMID 22730630.
- Wiktorowska-Owczarek A, Berezińska M, Nowak JZ (2015). "PUFAs: Structures, Metabolism and Functions". Advances in Clinical and Experimental Medicine : Official Organ Wroclaw Medical University. 24 (6): 931–41. PMID 26771963.
- Tanaka N, Yamaguchi H, Furugen A, Ogura J, Kobayashi M, Yamada T, Mano N, Iseki K (2014). "Quantification of intracellular and extracellular eicosapentaenoic acid-derived 3-series prostanoids by liquid chromatography/electrospray ionization tandem mass spectrometry". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 91 (3): 61–71. doi:10.1016/j.plefa.2014.04.005. PMID 24996760.
- Das UN (1983). "Prostaglandins and gene action: possible relevance to the effect of PG system on leukocyte alkaline phosphatase enzyme activity". Medical Hypotheses. 11 (2): 185–94. PMID 6684205.
- Prasad KN, Hovland AR, Cole WC, Prasad KC, Nahreini P, Edwards-Prasad J, Andreatta CP (2000). "Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale". Clinical Neuropharmacology. 23 (1): 2–13. PMID 10682224.
- Xu Y, Qian SY (2014). "Anti-cancer activities of ω-6 polyunsaturated fatty acids". Biomedical Journal. 37 (3): 112–9. doi:10.4103/2319-4170.131378. PMC . PMID 24923568.
- 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. doi:10.1177/154405910308200202. PMID 12562878.
- 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. doi:10.1016/j.prostaglandins.2004.03.005. PMID 15290791.
- 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. doi:10.1016/j.nut.2003.09.018. PMID 14698023.
- Czerska M, Zieliński M, Gromadzińska J (2016). "Isoprostanes - A novel major group of oxidative stress markers". International Journal of Occupational Medicine and Environmental Health. 29 (2): 179–90. doi:10.13075/ijomeh.1896.00596. PMID 26670350.
- Cuyamendous C, de la Torre A, Lee YY, Leung KS, Guy A, Bultel-Poncé V, Galano JM, Lee JC, Oger C, Durand T (2016). "The novelty of phytofurans, isofurans, dihomo-isofurans and neurofurans: Discovery, synthesis and potential application". Biochimie. doi:10.1016/j.biochi.2016.08.002. PMID 27519299.
- 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. PMID 10869392.
- 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. doi:10.1016/0002-9378(93)90362-m. PMID 8475962.
- 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. doi:10.1159/000053688. PMID 11306946.
- 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. doi:10.1054/plef.1999.0074. PMID 10477044.
- University of Kansas Medical Center (2004). "Eicosanoids and Inflammation" (PDF). Retrieved 2007-01-05.[dead link]
- Cyrus, Tillmann; Witztum, Joseph L.; Rader, Daniel J.; Tangirala, Rajendra; Fazio, Sergio; Linton, Macrae F.; Funk, Colin D. (June 1999). "Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice". J Clin Invest. 103 (11): 1597–1604n. doi:10.1172/JCI5897. PMC . PMID 10359569.
- Schewe T. (Mar–Apr 2002). "15-lipoxygenase-1: a prooxidant enzyme". Biol Chem. 383 (3–4): 365–74. doi:10.1515/BC.2002.041. PMID 12033428.
- Powell, W. S.; Rokach, J (2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Progress in Lipid Research. 52 (4): 651–65. doi:10.1016/j.plipres.2013.09.001. PMID 24056189.
- Pace-Asciak, C. R. (2009). "The hepoxilins and some analogues: A review of their biology". British Journal of Pharmacology. 158 (4): 972–81. doi:10.1111/j.1476-5381.2009.00168.x. PMC . PMID 19422397.
- Dobrian, A. D.; Lieb, D. C.; Cole, B. K.; Taylor-Fishwick, D. A.; Chakrabarti, S. K.; Nadler, J. L. (2011). "Functional and pathological roles of the 12- and 15-lipoxygenases". Progress in Lipid Research. 50 (1): 115–31. doi:10.1016/j.plipres.2010.10.005. PMC . PMID 20970452.
- Ivanov, I; Kuhn, H; Heydeck, D (2015). "Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15)". Gene. 573 (1): 1–32. doi:10.1016/j.gene.2015.07.073. PMID 26216303.
- Wittwer, J; Hersberger, M (2007). "The two faces of the 15-lipoxygenase in atherosclerosis". Prostaglandins, Leukotrienes and Essential Fatty Acids. 77 (2): 67–77. doi:10.1016/j.plefa.2007.08.001. PMID 17869078.
- Kroetz DL, Xu F (2005). "Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation". Annual Review of Pharmacology and Toxicology. 45: 413–38. doi:10.1146/annurev.pharmtox.45.120403.100045. PMID 15822183.
- Yang, L; Mäki-Petäjä, K; Cheriyan, J; McEniery, C; Wilkinson, I. B. (2015). "The role of epoxyeicosatrienoic acids in the cardiovascular system". British Journal of Clinical Pharmacology. 80 (1): 28–44. doi:10.1111/bcp.12603. PMC . PMID 25655310.
- Spector, A. A.; Kim, H. Y. (2015). "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 356–65. doi:10.1016/j.bbalip.2014.07.020. PMC . PMID 25093613.
- Fer, M; Dréano, Y; Lucas, D; Corcos, L; Salaün, J. P.; Berthou, F; Amet, Y (2008). "Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450". Archives of Biochemistry and Biophysics. 471 (2): 116–25. doi:10.1016/j.abb.2008.01.002. PMID 18206980.
- Shahabi, P; Siest, G; Meyer, U. A.; Visvikis-Siest, S (2014). "Human cytochrome P450 epoxygenases: Variability in expression and role in inflammation-related disorders". Pharmacology & Therapeutics. 144 (2): 134–61. doi:10.1016/j.pharmthera.2014.05.011. PMID 24882266.
- Frömel, T; Kohlstedt, K; Popp, R; Yin, X; Awwad, K; Barbosa-Sicard, E; Thomas, A. C.; Lieberz, R; Mayr, M; Fleming, I (2013). "Cytochrome P4502S1: A novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques". Basic Research in Cardiology. 108 (1): 319. doi:10.1007/s00395-012-0319-8. PMID 23224081.
- Fleming, I (2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID 25244930.
- Westphal, C; Konkel, A; Schunck, W. H. (2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators. 96 (1–4): 99–108. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326.
- Pace-Asciak CR; Hahn S; Diamandis EP; Soleas G; Goldberg DM. (31 March 1995). "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. doi:10.1016/0009-8981(95)06045-1. PMID 7554275.
- Fritsche, Kevin (August 2006). "Fatty Acids as Modulators of the Immune Response". Annual Review of Nutrition. 26: 45–73. doi:10.1146/annurev.nutr.25.050304.092610. PMID 16848700. Retrieved 2007-01-11.
- National Institute of Health (2005-08-01). "Omega-3 fatty acids, fish oil, alpha-linolenic acid". Archived from the original on May 3, 2006. Retrieved March 26, 2006.
- 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. doi:10.1016/j.biocel.2003.08.006. 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. PMID 2820055. Retrieved 2007-01-22.
- Samuelsson B (May 1983). "Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation". Science. 220 (4597): 568–575. doi:10.1126/science.6301011. PMID 6301011.
- Capra V (2004). "Molecular and functional aspects of human cysteinyl leukotriene receptors". Pharmacol Res. 50 (1): 1–11. doi:10.1016/j.phrs.2003.12.012. PMID 15082024.
- Boyce J (2005). "Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications". Chem Immunol Allergy. Chemical Immunology and Allergy. 87: 59–79. doi:10.1159/000087571. ISBN 3-8055-7948-9. PMID 16107763.
- Burr, G.O.; 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): 207–10. doi:10.1016/0304-4165(64)90145-x. PMID 14201168.
- Vane, J. R. (June 23, 1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs". Nature New Biol. 231 (25): 232–5. doi:10.1038/newbio231232a0. PMID 5284360.