Eicosanoid


Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids that are, similar to arachidonic acid, 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.
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, one series derived from the ω-3 PUFA, and one series derived from the ω-9 PUFA. 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.

Nomenclature

Fatty acid sources

"Eicosanoid" is the collective term for straight-chain polyunsaturated fatty acids of 20 carbon units in length that have been metabolized or otherwise converted to oxygen-containing products. The PUFA precursors to the eicosanoids include:
A particular eicosanoid is denoted by a four-character abbreviation, composed of:
The stereochemistry of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters. For hydroperoxy and hydroxy eicosanoids an S or R designates the chirality of their substituents -, 5S-hydroxy-, and 5-hydroxy-eicosatetraenoic acid] is given the trivial names of 5S-HETE, 5-HETE, 5S-HETE, or 5. Since eicosanoid-forming enzymes commonly make S isomer products either with marked preference or essentially exclusively, the use of S/R designations has often been dropped. 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.

Classic eicosanoids

Current usage limits the term eicosanoid to:

Hydroxyeicosatetraenoic acids, leukotrienes, eoxins and prostanoids are sometimes termed "classic eicosanoids"

Nonclassic 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:
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-hydroxy-6E,8Z,11Z-eicosatrienoic acid, 5-oxo-6,8,11-eicosatrienoic acid, LTA3, and LTC3 involve the same enzymatic pathways that make their arachidonic acid-derived analogs.

Biosynthesis

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, 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 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.

Peroxidation and reactive oxygen species

Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways add molecular oxygen. Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidations proceed with high stereoselectivity.
Four families of enzymes initiate or contribute to the initiation of the catalysis of fatty acids to eicosanoids:
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, bacterial cytochrome P450, or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series resolvins . 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 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 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.
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Prostanoid pathways

Both COX1 and COX2 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 Prostaglandin D2 synthase which converts PGH2 to PGD2 thromboxane synthase which converts PGH2 to TXA2 ''' Prostacyclin synthase which converts PGH2 to PGI2.
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.

Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways

See Leukotriene#Biosynthesis, Hydroxyeicosatetraenoic acid, and Eoxin#Human biosynthesis.
The enzyme 5-lipoxygenase converts arachidonic acid into 5-hydroperoxyeicosatetraenoic acid, which may be released and rapidly reduced to 5-hydroxyeicosatetraenoic acid by ubiquitous cellular glutathione-dependent peroxidases. Alternately, ALOX5 uses its LTA synthase activity to act convert 5-HPETE to leukotriene A4. LTA4 is then metabolized either to LTB4 by Leukotriene A4 hydrolase or Leukotriene C4 by either LTC4 synthase or microsomal glutathione S-transferase 2. Either of the latter two enzymes act to attach the sulfur of cysteine's thio- group in the tripeptide glutamate-cysteine-glycine to carbon 6 of LTA4 thereby forming LTC4. After release from its parent cell, the glutamate and glycine residues of LTC4 are removed step-wise by gamma-glutamyltransferase and a dipeptidase to form sequentially LTD4 and LTE4. The decision to form LTB4 versus LTC4 depends on the relative content of LTA4 hydrolase versus LTC4 synthase.
The enzyme arachidonate 12-lipoxygenase metabolizes arachidonic acid to the S stereoisomer of 12-hydroperoxyeicosatetraenoic acid which is rapidly reduced by cellular peroxidases to the S stereoisomer of 12-hydroxyeicosatetraenoic acid or further metabolized to hepoxilins such as HxA3 and HxB.
The enzymes 15-lipoxygenase-1 and 15-lipoxygenase-2 metabolize arachidonic acid to the S stereoisomer of 15-Hydroperoxyeicosatetraenoic acid which is rapidly reduced by cellular peroxidases to the S stereoisomer of 15-Hydroxyicosatetraenoic acid. The 15-lipoxygenases 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 microsome-bound ω-hydroxylases metabolize arachidonic acid to 20-Hydroxyeicosatetraenoic acid and 19-hydroxyeicosatetraenoic acid by an omega oxidation reaction.

Epoxyeicosanoid pathway

The human cytochrome P450 epoxygenases, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 metabolize arachidonic acid to the non-classic Epoxyeicosatrienoic acids 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 viz., 17,18-EEQ, 14,15-EEQ, 11,12-EEQ. 8,9-EEQ, and 5,6-EEQ.

Function, pharmacology, and clinical significance

The following table lists a sampling of the major eicosanoids that possess clinically relevant biological activity, the cellular receptors that they stimulate or, where noted, antagonize to attain this activity, some of the major functions which they regulate in humans and mouse models, and some of their relevancies to human diseases.
EicosanoidTargeted receptorsFunctions regulatedClinical relevancy
PGE2PTGER1, PTGER2, PTGER3, PTGER4inflammation; fever; pain perception; allodynia; parturitionNSAIDs inhibit its production to reduce inflammation, fever, and pain; used to promote labor in childbirth; an Abortifacient
PGD2Prostaglandin DP1 receptor 1, Prostaglandin DP2 receptorallergy reactions; allodynia; hair growthNSAIDs may target it to inhibit allodynia and male-pattern hair loss
TXA2Thromboxane receptor α and βblood platelet aggregation; blood clotting; allergic reactionsNSAIDs inhibit its production to reduce incidence of strokes and heart attacks
PGI2Prostacyclin receptorplatelet aggregation, vascular smooth muscle contractionPGI2 analogs used to treat vascular disorders like pulmonary hypertension, Raynaud's syndrome, and Buerger's disease
15-d-Δ12,14-PGJ2PPARγ, Prostaglandin DP2 receptorinhibits inflammation and cell growthInhibits diverse inflammatory responses in animal models; structural model for developing anti-inflammatory agents
20-HETE?vasoconstriction, inhibits plateletsinactivating mutations in the 20-HETE-forming enzyme, CYP2U1, associated with Hereditary spastic paraplegia
5-Oxo-ETEOXER1chemotactic factor for and activator of eosinophilsstudies needed to determine if inhibiting its production or action inhibits allergic reactons
LTB4LTB4R, LTB4R2chemotactic factor for and activator of leukocytes; inflammationstudies to date shown no clear benefits of LTB4 receptor antagonists for human inflammatory diseases
LTC4CYSLTR1, CYSLTR2, GPR17vascular permeability; vascular smooth muscle contraction; allergyantagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions
LTD4CYSLTR1, CYSLTR2, GPR17vascular permeability; vascular smooth muscle contraction; allergyantagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions
LTE4GPR99increases vascular permeability and airway mucin secretionthought to contribute to asthma as well as other allergic and allergic-like reactions
LxA4FPR2inhibits functions of pro-inflammatory cellsSpecialized pro-resolving mediators class of inflammatory reaction suppressors
LxB4FPR2, GPR32, AHRinhibits functions of pro-inflammatory cellsSpecialized pro-resolving mediators class of inflammatory reaction suppressors
RvE1CMKLR1, inhibits BLT, TRPV1, TRPV3, NMDAR, TNFRinhibits functions of pro-inflammatory cellsSpecialized pro-resolving mediators class of inflammatory reaction suppressors; also suppresses pain perception
RvE2CMKLR1, receptor antagonist of BLTinhibits functions of pro-inflammatory cellsSpecialized pro-resolving mediators class of inflammatory reaction suppressors
14,15-EET?vasodilation, inhibits platelets and pro-inflammatory cellsrole in human disease not yet proven

Prostanoids

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, 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.
MedicineTypeMedical condition or useMedicineTypeMedical condition or use
AlprostadilPGE1Erectile dysfunction, maintaining a patent ductus arteriosus in the fetusBeraprostPGI1 analogPulmonary hypertension, avoiding reperfusion injury
BimatoprostPGF2α analogGlaucoma, ocular hypertensionCarboprostPGF2α analogLabor induction, abortifacient in early pregnancy
DinoprostonePGE2labor inductionIloprostPGI2 analogpulmonary artery hypertension
LatanoprostPGF2α analogGlaucoma, ocular hypertensionMisoprostolPGE1 analogstomach ulcers labor induction, abortifacient
TravoprostPGF2α analogGlaucoma, ocular hypertensionU46619Longer lived TX analog Longer lived TX analogResearch only

Cyclopentenone prostaglandins

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.

HETEs and oxo-ETEs

As indicated in their individual Wikipedia pages, 5-hydroxyeicosatetraenoic acid, 5-oxo-eicosatetraenoic acid, 12-Hydroxyeicosatetraenoic acid, 15-Hydroxyeicosatetraenoic acid, and 20-Hydroxyeicosatetraenoic acid show numerous activities in animal and human cells as well as in animal models that are related to, for example, inflammation, allergic reactions, cancer cell growth, blood flow to tissues, and/or blood pressure. However, their function and relevancy to human physiology and pathology have not as yet been shown.

Leukotrienes

The three cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are potent bronchoconstrictors, increasers of vascular permeability in postcapillary venules, and stimulators of mucus secretion that are released from the lung tissue of asthmatic subjects exposed to specific allergens. They play a pathophysiological role in diverse types of immediate hypersensitivity reactions. Drugs that block their activation of the CYSLTR1 receptor viz., montelukast, zafirlukast, and pranlukast, are used clinically as maintenance treatment for allergen-induced asthma and rhinitis; nonsteroidal anti-inflammatory drug-induced asthma and rhinitis ; exercise- and cold-air induced asthma ; and childhood sleep apnea due to adenotonsillar hypertrophy. When combined with antihistamine drug therapy, they also appear useful for treating urticarial diseases such as hives.

Lipoxins and epi-lipoxins

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.

Eoxins

The eoxins 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.

Resolvin metabolites of eicosapentaenoic acid

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 for the treatment of the inflammation-based dry eye syndrome; along with this study, other clinical trials 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, the hydroxyeicosapentaenoic acids, and the 5-series LTs. 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.

Epoxyeicosanoids

The epoxy eicostrienoic acids —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 ω-3 and ω-6 series

sits at the head of the "arachidonic acid cascade" – more than twenty 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 provides the most important competing cascade. DGLA 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 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
alter membrane composition and function, including the composition of lipid rafts;
change cytokine biosynthesis; and directly activate gene transcription. Of these, the action on eicosanoids is the best explored.

Mechanisms of ω-3 action

In general, the eicosanoids derived from AA promote inflammation, and those from EPA and from GLA 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:
, the cardinal signs of inflammation have been known as: calor, dolor, tumor, and rubor. 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.

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.
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.