There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and eoxins. For each subfamily, there is the potential to have at least 4 separate series of metabolites, two series derived from ω-6 PUFAs (arachidonic and dihomo-gamma-linolenic acids), one series derived from the ω-3 PUFA (eicosapentaenoic acid), and one series derived from the ω-9 PUFA (mead acid). This subfamily distinction is important. Mammals, including humans, are unable to convert ω-6 into ω-3 PUFA. In consequence, tissue levels of the ω-6 and ω-3 PUFAs and their corresponding eicosanoid metabolites link directly to the amount of dietary ω-6 versus ω-3 PUFAs consumed. Since certain of the ω-6 and ω-3 PUFA series of metabolites have almost diametrically opposing physiological and pathological activities, it has often been suggested that the deleterious consequences associated with the consumption of ω-6 PUFA-rich diets reflects excessive production and activities of ω-6 PUFA-derived eicosanoids, while the beneficial effects associated with the consumption of ω-3 PUFA-rich diets reflect the excessive production and activities of ω-3 PUFA-derived eicosanoids. In this view, the opposing effects of ω-6 PUFA-derived and ω-3 PUFA-derived eicosanoids on key target cells underlie the detrimental and beneficial effects of ω-6 and ω-3 PUFA-rich diets on inflammation and allergy reactions, atherosclerosis, hypertension, cancer growth, and a host of other processes.
A subscript or plain script number following the designated eicosanoid's trivial name indicates the number of its double bonds. Examples are:
The EPA-derived prostanoids have three double bonds (e.g. PGG3 or PGG3) while leukotrienes derived from EPA have five double bonds (e.g. LTB5 or LTB5).
The AA-derived prostanoids have two double bonds (e.g. PGG2 or PGG2) while their AA-derived leukotrienes have four double bonds (e.g. LTB4 or LTB4).
Hydroperoxy-, hydroxyl-, and oxo-eicosanoids possess a hydroperoxy (-OOH), hydroxy (-OH), or oxygen atom (=O) substituents link to a PUFA carbon by a single (-) or double (=) bond. Their trivial names indicate the substituent as: Hp or HP for a hydroperoxy residue (e.g. 5-hydroperooxy-eicosatraenoic acid or 5-HpETE or 5-HPETE); H for a hydroxy residue (e.g. 5-hydroxy-eicosatetraenoic acid or 5-HETE); and oxo- for an oxo residue (e.g. 5-oxo-eicosatetraenioic acid or 5-oxo-ETE or 5-oxoETE). The number of their double bounds is indicated by their full and trivial names: AA-derived hydroxy metabolites have four (i.e. 'tetra' or 'T') double bonds (e.g. 5-hydroxy-eicosatetraenoic acid or 5-HETE; EPA-derived hydroxy metabolites have five ('penta' or 'P') double bonds (e.g. 5-hydroxy-eicosapentaenoic acid or 5-HEPE); and DGLA-derived hydroxy metabolites have three ('tri' or 'Tr') double bonds (e.g. 5-hydroxy-eicosatrienoic acid or 5-HETrE).
The stereochemistry of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters (e.g. PGF2α versus PGF2β). For hydroperoxy and hydroxy eicosanoids an S or R designates the chirality of their substituents (e.g. 5S-hydroxy-eicosateteraenoic acid [also termed 5(S)-, 5S-hydroxy-, and 5(S)-hydroxy-eicosatetraenoic acid] is given the trivial names of 5S-HETE, 5(S)-HETE, 5S-HETE, or 5(S)-HETE). Since eicosanoid-forming enzymes commonly make Sisomer products either with marked preference or essentially exclusively, the use of S/R designations has often been dropped (e.g. 5S-HETE is 5-HETE). Nonetheless, certain eicosanoid-forming pathways do form R isomers and their S versus R isomeric products can exhibit dramatically different biological activities. Failing to specify S/R isomers can be misleading. Here, all hydroperoxy and hydroxy substituents have the S configuration unless noted otherwise.
Current usage limits the term eicosanoid to:
ω-6 Series eicosanoids derived from arachidonic acid:
PGA1, PGA2 (see 'prostanoid, PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2.
ω-6 Series eicosanoids derived from dihomo-gamma-linolenic acid. These metabolites 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. They the following:
Other ω-3 series eicosapentaenoic acid-derived eicosanoids 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 (HEPE is hydroxy-eicsapentaenoic acid):
Hydroxyeicosatetraenoic acids, leukotrienes, eoxins and prostanoids are sometimes termed "classic eicosanoids"
In contrast to the classic eicosanoids, several other classes of PUFA metabolites have been termed 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'. These included the following classes:
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.
Metabolism of eicosapentaenoic acid to HEPEs, leukotrienes, prostanoids, and epoxyeicosatetraenoic acids as well as the metabolism of dihomo-gamma-linolenic acid to prostanoids and mead acid to 5(S)-hydroxy-6E,8Z,11Z-eicosatrienoic acid (5-HETrE), 5-oxo-6,8,11-eicosatrienoic acid (5-oxo-ETrE), LTA3, and LTC3 involve the same enzymatic 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 acid. 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. cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.
Lipoxygenases (LOXs): 5-Lipoxygenase (5-LOX or ALOX5) initiates the metabolism of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) which then may be rapidly reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) or further metabolized to the leukotrienes (e.g. LTB4 and LTC4); 5-HETE may be oxidized to 5-oxo-eicosatetraenoic acid (5-oxo-ETE). In similar fashions, 15-lipoxygenase (15-lipoxygenase 1, 15-LOX, 15-LOX1, or ALOX15) initiates the metabolism of arachidonic acid to 15-HpETE, 15-HETE, eoxins, 8,15-dihydroxyeicosatetraenoic acid (i.e. 8,15-DiHETE), and 15-oxo-ETE and 12-lipoxygenase (12-LOX or ALOX12) initiates the metabolism of arachidonic acid to 12-HpETE, 12-HETE, hepoxilins, and 12-oxo-ETE. These enzymes also initiate the metabolism of; a) eicosapentaenoic acid to analogs of the arachidonic acid metabolites that contain 5 rather than four double bonds, e.g. 5-hydroxy-eicosapentaenoic acid (5-HEPE), LTB5, LTC5, 5-oxo-EPE, 15-HEPE, and 12-HEPE; b) the three double bond-containing dihomo-γ-linolenic acid to products that contain 3 double bonds, e.g. 8-hydroxy-eicosatrienoic acid (8-HETrE), 12-HETrE, and 15-HETrE (this fatty acid cannot be converted to leukotrienes); and the three double bond-containing mead acid (by ALOX5) to 5-hydroperoxy-eicosatrienoic acid (5-HpETrE), 5-HETrE, and 5-oxo-HETrE. In the most studied of these pathways, ALOX5 metabolizes eicosapentaenoic acid to 5-hydroperoxyeicosapentaenoic acid (5-HpEPE), 5-HEPE, and LTB5, and 5-oxo-EPE, all of which are less active than there arachidonic acid analogs. Since eicosapentaenoic acid competes with arachidonic acid for ALOX5, production of the eicosapentaenoate metabolites leads to a reduction in the eicosatetraenoate metabolites and therefore reduction in the latter metabolites' signaling. The initial mono-hydroperoxy and mono-hydroxy products made by the aforementioned lipoxygenases have their hydroperosy and hydroxyl residues positioned in the Schiral configuration and are more properly termed 5S-HpETE, 5S-HETE, 12S-HpETE, 12S-HETE, 15S-HpETE and, 15S-HETE. ALOX12B (i.e. arachidonate 12-lipoxygenase, 12R type) forms R chirality products, i.e. 12R-HpETE and 12R-HETE. Similarly, ALOXE3 (i.e. epidermis-type lipoxygenase 3 or eLOX3) metabolizes arachidonic acid to 12R-HpETE and 12R-HETE; however these are minor products that this enzyme forms only under a limited set of conditions. ALOXE3 preferentially metabolizes arachidonic acid to hepoxilins.
Epoxygenases: these are cytochrome P450 enzymes which generate nonclassic eicosanoidepoxides derived from: a) arachidonic acid viz., 5,6-epoxy-eicosatrienoic acid (5,6-EET), 8,9-EET, 11,12-EET, and 14,15-EET (see Epoxyeicosatrienoic acid); b) eicosapentaenoic acid viz., 5,6,-epoxy-eicosatetraenoic acid (5,6-EEQ), 8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 17,18-EEQ (see Epoxyeicosatetraenoic acid); c) di-homo-γ-linolenic acid viz., 8,9-epoxy-eicosadienoic acid (8,9-EpEDE), 11,12-EpEDE, and 14,15-EpEDE; and d) adrenic acid viz., 7,8-epox-eicosatrienoic acid (7,8-EpETrR), 10,11-EpTrE, 13,14-EpTrE, and 16,17-EpETrE. All of these epoxides are converted, sometimes rapidly, to their dihydroxy metabolites, by various cells and tissues. For example, 5,6-EET is converted to 5,6-dihydroxy-eicosatrienoic acid (5,6-DiHETrE), 8,9-EEQ to 8,9-dihydroxy-eicosatetraenoic acid (8,9-DiHETE, 11,12-EpEDE to 11,12-dihydroxy-eicosadienoic acid (11,12DiHEDE), and 16,17-EpETrE to 16,17-dihydroxy-eicosatrienoic acid (16,17-DiETrE
Two different enzymes may act in series on a PUFA to form more complex metabolites. For example, ALOX5 acts with ALOX12 or aspirin-treated COX-2 to metabolize arachidonic acid to lipoxins and with cytochrome P450 monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series resolvins (RvEs) (see Specialized pro-resolving mediators). When this occurs with enzymes located in different cell types and involves the transfer of one enzyme's product to a cell which uses the second enzyme to make the final product it is referred to as transcellular metabolism or transcellular biosynthesis.
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).
Structures of selected eicosanoids
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.
Prostacyclin I2. The second ring distinguishes it from the prostaglandins.
Leukotriene E4, an example of a cysteinyl leukotriene.
Both COX1 and COX2 (also termed prostaglandin-endoperoxide synthase-1 (PTGS1) and PTGS2, respectively) metabolize arachidonic acid by adding molecular O2 between carbons 9 and 11 to form an endoperoxide bridge between these two carbons, adding molecular O2 to carbon 15 to yield a 15-hydroperoxy product, creating a carbon-carbon bond between carbons 8 and 12 to create a cyclopentane ring in the middle of the fatty acid, and in the process making PGG2, a product that has two fewer double bonds than arachidonic acid. The 15-hydroperoxy residue of PGG2 is then reduced to a 15-hydroxyl residue thereby forming PGH2. PGH2 is the parent prostanoid to all other prostanoids. It is metabolized by (see diagram in Prostanoids: a) the Prostaglandin E synthase pathway in which any one of three isozymes, PTGES, PTGES2, or PTGES3, convert PGH2 to PGE2 (subsequent products of this pathway include PGA2 and PGB2 (see Prostanoid#Biosynthesis); b) PGF synthase which converts PGH2 to PGF2α; c)Prostaglandin D2 synthase which converts PGH2 to PGD2 (subsequent products in this pathway include 15-dPGJ2 (see Cyclopentenone prostaglandin); d)thromboxane synthase which converts PGH2 to TXA2 (subsequent products in this pathway include TXB2); and e)Prostacyclin synthase which converts PGH2 to PGI2 (subsequent products in this pathway include 6-keto-PGFα. These pathways have been shown or in some cases presumed to metabolize eicosapentaenoic acid to eicosanoid analogs of the sited products that have three rather than two double bonds and therefore contain the number 3 in place of 2 attached to their names (e.g. PGE3 instead of PGE2).
The PGE2, PGE1, and PGD2 products formed in the pathways just cited can undergo a spontaneous dehydration reaction to form PGA2, PGA1, and PGJ2, respectively; PGJ2 may then undergo a spontaneous isomerization followed by a dehydration reaction to form in series Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2.
PGH2 has a 5-carbon ring bridged by molecular oxygen. Its derived PGS have lost this oxygen bridge and contain a single, unsaturated 5-carbon ring with the exception of thromboxane A2 which possesses a 6-member ring consisting of one oxygen and 5 carbon atoms. The 5-carbon ring of prostacyclin is conjoined to a second ring consisting of 4 carbon and one oxygen atom. And, the 5 member ring of the cyclopentenone prostaglandins possesses an unsaturated bond in a conjugated system with a carbonyl group that causes these PGs to form bonds with a diverse range of bioactive proteins (for more see the diagrams at Prostanoid).
Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways
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(S)-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 15-Hydroxyicosatetraenoic acid (15(S)-HETE). The 15-lipoxygenases (particularly ALOX15) may also act in series with 5-lipoxygenase, 12-lipoxygenase, or aspirin-treated COX2 to form the lipoxins and epi-lipoxins or with P450 oxygenases or aspirin-treated COX2
to form Resolvin E3 (see Specialized pro-resolving mediators#EPA-derived resolvins.
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 converting 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, pharmacology, and clinical significance
The following table lists a sampling of the major eicosanoids that possess clinically relevant biological activity, the cellular receptors (see Cell surface receptor) that they stimulate or, where noted, antagonize to attain this activity, some of the major functions which they regulate (either promote or inhibit) in humans and mouse models, and some of their relevancies to human diseases.
Many of the prostanoids are known to mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain, and fever. Inhibition of COX-1 and/or the inducible COX-2 isoforms, is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. Prostanoids also activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, and directly influence gene transcription.
Prostanoids have numerous other relevancies to clinical medicine as evidence by their use, the use of their more stable pharmacological analogs, of the use of their receptor antagonists as indicated in the following chart.
PGA1, PGA2, PGJ2, Δ12-PGJ2, and 15-deox-Δ12,14-PGJ2 exhibit a wide range of anti-inflammatory and inflammation-resolving actions in diverse animal models. They therefore appear to function in a manner similar to Specialized pro-resolving mediators although one of their mechanisms of action, forming covalent bonds with key signaling proteins, differs from those of the specialized pro-resolving mediators.
LxA4, LxB4, 15-epi-LxA4, and 15-epi-LXB4, like other members of the specialized pro-resolving mediators) class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. In a randomized controlled trial, AT-LXA4 and a comparatively stable analog of LXB4, 15R/S-methyl-LXB4, reduced the severity of eczema in a study of 60 infants and, in another study, inhaled LXA4 decreased LTC4-initiated bronchoprovocation in patients with asthma.
The eoxins (EXC4, EXD4, EXE5) are newly described. They stimulate vascular permeability in an ex vivo human vascular endothelial model system, and in a small study of 32 volunteers EXC4 production by eosinophils isolated from severe and aspirin-intolerant asthmatics was greater than that from healthy volunteers and mild asthmatic patients; these findings have been suggested to indicate that the eoxins have pro-inflammatory actions and therefore potentially involved in various allergic reactions. Production of eoxins by Reed-Sternburg cells has also led to suggestion that they are involve in Hodgkins disease. However, the clinical significance of eoxins has not yet been demonstrated.
RvE1, 18S-RvE1, RvE2, and RvE3, like other members of the specialized pro-resolving mediators) class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. A synthetic analog of RvE1 is in clinical phase III testing (see Phases of clinical research) for the treatment of the inflammation-based dry eye syndrome; along with this study, other clinical trials (NCT01639846, NCT01675570, NCT00799552 and NCT02329743) using an RvE1 analogue to treat various ocular conditions are underway. RvE1 is also in clinical development studies for the treatment of neurodegenerative diseases and hearing loss.
Other metabolites of eicosapentaenoic acid
The metabolites of eicosapentaenoic acid that are analogs of their arachidonic acid-derived prostanoid, HETE, and LT counterparts include: the 3-series prostanoids (e.g. PGE3, PGD3, PGF3α, PGI3, and TXA3), the hydroxyeicosapentaenoic acids (e.g. 5-HEPE, 12-HEPE, 15-HEPE, and 20-HEPE), and the 5-series LTs (e.g. LTB5, LTC5, LTD5, and LTE5). Many of the 3-series prostanoids, the hydroxyeicosapentaenoic acids, and the 5-series LT have been shown or thought to be weaker stimulators of their target cells and tissues than their arachidonic acid-derived analogs. They are proposed to reduce the actions of their aracidonate-derived analogs by replacing their production with weaker analogs. Eicosapentaenoic acid-derived counterparts of the Eoxins have not been described.
The epoxy eicostrienoic acids (or EETs)—and, presumably, 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, and 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.
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
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.
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
EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At each step, the ω-3 and ω-6 cascades compete for the enzymes.
In general, the eicosanoids derived from AA promote inflammation, and those from EPA and from GLA (via DGLA) are less inflammatory, or inactive, or even anti-inflammatory and pro-resolving.
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.
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.
^Prostacyclin—PGI—was previously classified as prostaglandin and retains its old PGI2 identifier.
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