Eicosanoid - Knowledge

161:. For each subfamily, there is the potential to have at least 4 separate series of metabolites, two series derived from the 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 1551:, 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 20: 1798: 3731: 1791: 1839: 3525:). 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 arachidonate-derived analogs by replacing their production with weaker analogs. Eicosapentaenoic acid-derived counterparts of the eoxins have not been described. 1846: 1805: 2046:(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. PGE 3266:

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

442:

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

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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 bond than their arachidonic acid-derived analogs. They include (HEPE is hydroxyeicosapentaenoic acid):

1651:

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

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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

1222:

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),

1704:

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

853:ω−6 series eicosanoids derived from dihomo-gamma-linolenic acid. These metabolites are analogs of arachidonic acid-derived eicosanoids but lack a double bond between carbons 5 and 6 and therefore have 1 less double bond than their arachidonic acid-derived analogs. They are the following: 3481:; 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. 1546:

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

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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

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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

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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".

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James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE (2013). "The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma".

1701:). 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. 2368:(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 1255:. 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. 3472:

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

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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

6008:

Frömel, T; Kohlstedt, K; Popp, R; Yin, X; Awwad, K; Barbosa-Sicard, E; Thomas, AC; Lieberz, R; Mayr, M; Fleming, I (2013). "Cytochrome P4502S1: A novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques".

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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".

2432:) 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. 2941:. 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. 4732:

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".

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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 LTB

3609:

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

1652:(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. 7521:

Oussalah A, Mayorga C, Blanca M, Barbaud A, Nakonechna A, Cernadas J, Gotua M, Brockow K, Caubet JC, Bircher A, Atanaskovic M, Demoly P, K Tanno L, Terreehorst I, Laguna JJ, Romano A, Guéant JL (April 2016).

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Ahmad S, Thulasingam M, Palombo I, Daley DO, Johnson KA, Morgenstern R, Haeggström JZ, Rinaldo-Matthis A (2015). "Trimeric microsomal glutathione transferase 2 displays one third of the sites reactivity".

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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".

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Cruz JE, Ward A, Anthony S, Chang S, Bae HB, Hermes-DeSantis ER (2016). "Evidence for the Use of Epoprostenol to Treat Raynaud's Phenomenon With or Without Digital Ulcers: A Review of the Literature".

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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".

7935:

Calder PC (2014). "Biomarkers of immunity and inflammation for use in nutrition interventions: International Life Sciences Institute European Branch work on selection criteria and interpretation".

6531:

O'Connell C, Amar D, Boucly A, Savale L, Jaïs X, Chaumais MC, Montani D, Humbert M, Simonneau G, Sitbon O (2016). "Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension".

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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,

7021:

Chiang N, Serhan CN, Dahlén SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C (2006). "The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo".

4440:

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".

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Mitchell S, Balp MM, Samuel M, McBride D, Maurer M (2015). "Systematic review of treatments for chronic spontaneous urticaria with inadequate response to licensed first-line treatments".

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ETE). The number of their double bonds 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-eicosa

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Surh YJ, Na HK, Park JM, Lee HN, Kim W, Yoon IS, Kim DD (2011). "15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling".

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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".

5411:

Simopoulos AP (2010). "Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk".

3787:, 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. 1681:(20-HETE) but also to 16-HETE, 17-HETE, 18-HETE, and 19-HETE; they also metabolize eicosapentaenoic acid primarily to 20-hydroxy-eicosapentaenoic acid (20-HEPE) but also to 19-HEPE. 1685:

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

1756:) belong to families whose functions are involved largely with cellular detoxification. This suggests that eicosanoid signaling might have evolved from the detoxification of ROS. 2104:

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 A

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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. PGE

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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.

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Shinto, Lynne H.; Murchison, Charles F.; Silbert, Lisa C.; Dodge, Hiroko H.; Lahna, David; Rooney, William; Kaye, Jeffrey; Quinn, Joseph F.; Bowman, Gene L. (2024-08-01).

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Garza LA, Liu Y, Yang Z, Alagesan B, Lawson JA, Norberg SM, Loy DE, Zhao T, Blatt HB, Stanton DC, Carrasco L, Ahluwalia G, Fischer SM, FitzGerald GA, Cotsarelis G (2012).

1446:, which has 5 double bonds compared to the 4 double bonds of arachidonic acid, to prostanoid, prostacyclin, and thromboxane products that have three double bonds, e.g. PGE 3769:—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. 2399:

The human cytochrome P450 (CYP) epoxygenases, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 metabolize arachidonic acid to the non-classic

6631:

Citterio A, Arnoldi A, Panzeri E, D'Angelo MG, Filosto M, Dilena R, Arrigoni F, Castelli M, Maghini C, Germiniasi C, Menni F, Martinuzzi A, Bresolin N, Bassi MT (2014).

1610:-HETE; however these are minor products that this enzyme forms only under a limited set of conditions. ALOXE3 preferentially metabolizes arachidonic acid to hepoxilins. 5973:

Shahabi, P; Siest, G; Meyer, UA; Visvikis-Siest, S (2014). "Human cytochrome P450 epoxygenases: Variability in expression and role in inflammation-related disorders".

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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.

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Anwar Y, Sabir JS, Qureshi MI, Saini KS (2014). "5-lipoxygenase: a promising drug target against inflammatory diseases-biochemical and pharmacological regulation".

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Rossi A, Anzalone A, Fortuna MC, Caro G, Garelli V, Pranteda G, Carlesimo M (2016). "Multi-therapies in androgenetic alopecia: review and clinical experiences".

5140:"Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid" 3212:

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

214:) of 20 carbon units in length that have been metabolized or otherwise converted to oxygen-containing products. The PUFA precursors to the eicosanoids include: 3216:

although one of their mechanisms of action, forming covalent bonds with key signaling proteins, differs from those of the specialized pro-resolving mediators.

5048: 3301:

secretion that are released from the lung tissue of asthmatic subjects exposed to specific allergens. They play a pathophysiological role in diverse types of

4514: 8009: 3449:) are newly described. They stimulate vascular permeability in an ex vivo human vascular endothelial model system, and in a small study of 32 volunteers EXC 7478:

Kar M, Altıntoprak N, Muluk NB, Ulusoy S, Bafaqeeh SA, Cingi C (March 2016). "Antileukotrienes in adenotonsillar hypertrophy: a review of the literature".

1744:. The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes that are biosynthetic for eicosanoids (e.g., 1159: 761: 4238:

attached to the molecular skeleton. Letters indicate roughly the order the eicosanoids were first described in the literature. For diagrams for PG see

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makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also loses pro-inflammatory cytokines.

3346: 6052:

Fleming, I (2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease".

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Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter

186: 6735:"International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions" 4768:

Evans AR, Junger H, Southall MD, et al. (2000). "Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons".

3869: 1487:(5-LOX or ALOX5) initiates the metabolism of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) which then may be rapidly reduced to 4832:"Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization" 3638:

In the inflammatory response, two other groups of dietary fatty acids form cascades that parallel and compete with the arachidonic acid cascade.

265: 7313:

for "Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance" at

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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.

3718:

carriers, suggesting that this treatment may be beneficial for this specific group suggested fish oil supplements might help older adults fight

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The following table lists a sampling of the major eicosanoids that possess clinically relevant biological activity, the cellular receptors (see

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monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series

888: 8036: 1534:

to analogs of the arachidonic acid metabolites that contain 5 rather than four double bonds, e.g. 5-hydroxyeicosapentaenoic acid (5-HEPE), LTB

70:, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as 7614:

Wu SH, Chen XQ, Liu B, Wu HJ, Dong L (2013). "Efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in topical treatment of infantile eczema".

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Claesson HE (2009). "On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma".

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Hata AN, Breyer RM (2004). "Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation".

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Rådmark O, Werz O, Steinhilber D, Samuelsson B (2015). "5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease".

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Cyrus, Tillmann; Witztum, Joseph L.; Rader, Daniel J.; Tangirala, Rajendra; Fazio, Sergio; Linton, Macrae F.; Funk, Colin D. (June 1999).

8062:"ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial" 7711:"Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells" 4795:

O'Brien WF, Krammer J, O'Leary TD, Mastrogiannis DS (1993). "The effect of acetaminophen on prostacyclin production in pregnant women".

2314:. 5-LOX may also work in series with cytochrome P450 oxygenases or aspirin-treated COX2 to form Resolvins RvE1, RvE2, and 18S-RvE1 (see 4998: 1774: 1768: 495:

of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters (e.g. PGF

5187:

Capra V, Rovati GE, Mangano P, Buccellati C, Murphy RC, Sala A (2015). "Transcellular biosynthesis of eicosanoid lipid mediators".

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The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus. PGs and LTs may signal or regulate

928: 967:

In contrast to the classic eicosanoids, several other classes of PUFA metabolites have been termed 'novel', 'eicosanoid-like' or '

6927:"Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand" 3334: 3694:

patients. They also note more preliminary evidence showing that dietary ω−3 can ease symptoms in several psychiatric disorders.

8884: 7326:

Bos C, Richel D, Ritsema T, Peppelenbosch M, Versteeg H (2004). "Prostanoids and prostanoid receptors in signal transduction".

6432:"In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition" 6431: 6430:

Hoxha M, Buccellati C, Capra V, Garella D, Cena C, Rolando B, Fruttero R, Carnevali S, Sala A, Rovati GE, Bertinaria M (2016).

904: 1465:, which has three double bonds, to prostanoid, prostacyclin, and thromboxane products that have only one double bond, e.g. PGE 8625: 7709:

Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (January 2008).

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Romano M, Cianci E, Simiele F, Recchiuti A (2015). "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation".

6095:

Westphal, C; Konkel, A; Schunck, WH (2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?".

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allergic reactions. Production of eoxins by Reed–Sternberg cells cells has also led to suggestion that they are involved in

8150:

Bergström, S.; Danielsson, H.; Samuelsson, B. (1964). "The enzymatic formation of prostaglandin E2 from arachidonic acid".

7524:"Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review" 4241: 3338: 1131:; they include the following arachidonic acid-derived isoPs which are named based on their structural similarities to PGs: 4653:

Van Dyke TE, Serhan CN (2003). "Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases".

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stereoisomer of 15-hydroperoxyeicosatetraenoic acid (15(S)-HPETE) which is rapidly reduced by cellular peroxidases to the

1639:

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

4999:"The novelty of phytofurans, isofurans, dihomo-isofurans and neurofurans: Discovery, synthesis and potential application" 4318:

Straus DS, Glass CK (2001). "Cyclopentenone prostaglandins: new insights on biological activities and cellular targets".

3388: 3330: 3213: 1698: 1047: 3756:

Dietary ω−3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways, along the eicosanoid pathways:

2329:

stereoisomer of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) which is rapidly reduced by cellular peroxidases to the

2152: 949:

Hydroxy are derived form mead acid, is metabolized to the 3 double bond-containing analog of 5-HETE viz., 5-HETrE (see

8185:

Vane, J. R. (June 23, 1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs".

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and Mildred Burr showed that restricting fat from animals' diets led to a deficiency disease, and first described the

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biosynthesis; and (c) directly activate gene transcription. Of these, the action on eicosanoids is the best explored

3603: 4958:"Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation" 8847: 8254: 5055: 4997:

Cuyamendous C, de la Torre A, Lee YY, Leung KS, Guy A, Bultel-Poncé V, Galano JM, Lee JC, Oger C, Durand T (2016).

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inhibits diverse inflammatory responses in animal models; structural model for developing anti-inflammatory agents

1901:

to carbon 15 to yield a 15-hydroperoxy product, creating a carbon-carbon bond between carbons 8 and 12 to create a

1514:(15-lipoxygenase 1, 15-LOX, 15-LOX1, or ALOX15) initiates the metabolism of arachidonic acid to 15-HpETE, 15-HETE, 997: 950: 8013: 6633:"Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis" 5794:

Kroetz DL, Xu F (2005). "Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation".

411:

A subscript or plain script number following the designated eicosanoid's trivial name indicates the number of its

3509:), the hydroxyeicosapentaenoic acids (e.g. 5-HEPE, 12-HEPE, 15-HEPE, and 20-HEPE), and the 5-series LTs (e.g. LTB 3263: 3259: 3255: 3241: 3237: 3233: 2384: 2365: 2334: 1678: 993: 603: 599: 118:; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as 6632: 2831:

Specialized pro-resolving mediators class of inflammatory reaction suppressors; also suppresses pain perception

959:

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

8541: 3247: 3225: 2160: 1488: 1326:) appearing to be responsible for releasing the fatty acids under many conditions of cell activation. The cPLA 7361:

Samuelsson B (May 1983). "Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation".

3655: 3187: 3088: 2627: 2117:

that causes these PGs to form bonds with a diverse range of bioactive proteins (for more see the diagrams at

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Cacione, Daniel G.; Macedo, Cristiane R.; do Carmo Novaes, Frederico; Baptista-Silva, Jose Cc (4 May 2020).

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Dobrian, A. D.; Lieb, D. C.; Cole, B. K.; Taylor-Fishwick, D. A.; Chakrabarti, S. K.; Nadler, J. L. (2011).

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The figure shows the ω−3 and −6 synthesis chains, along with the major eicosanoids from AA, EPA, and DGLA.

3659: 2322: 2134: 2009: 1745: 1199: 814: 581: 3623:(AA; 20:4 ω−6) sits at the head of the "arachidonic acid cascade" – more than twenty eicosanoid-mediated 1647:

Dihomo-γ-linolenic acid viz., 8,9-epoxy-eicosadienoic acid (8,9-EpEDE), 11,12-EpEDE, and 14,15-EpEDE; and

3643: 3555:, and other blood vessels as well as on the kidney's reabsorption of sodium and water, and act to reduce 3474: 3392: 3251: 3229: 2089:

may then undergo a spontaneous isomerization followed by a dehydration reaction to form in series Δ12-PGJ

1507: 1484: 1203: 985: 335: 32: 2488:

inhibit its production to reduce inflammation, fever, and pain; used to promote labor in childbirth; an

8297: 8292: 6782:

Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE (2014).

6285:"Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia" 3538: 2600: 2506: 2502: 2417: 1640: 1631:

Arachidonic acid viz., 5,6-epoxy-eicosatrienoic acid (5,6-EET), 8,9-EET, 11,12-EET, and 14,15-EET (see

1335: 1124: 1101: 479:

E); and DGLA-derived hydroxy metabolites have three ('tri' or 'Tr') double bonds (e.g. 5-hydroxy-eicosa

211: 59: 4069:

Funk, Colin D. (30 November 2001). "Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology".

1970: 1876: 1462: 1294:), capable of releasing ω−6 and ω−3 fatty acids from membrane storage. These fatty acids are bound in 8618: 6831:

Cingi C, Muluk NB, Ipci K, Şahin E (2015). "Antileukotrienes in upper airway inflammatory diseases".

3591: 2254: 2218: 1989: 1909:, a product that has two fewer double bonds than arachidonic acid. The 15-hydroperoxy residue of PGG 8531: 8226: 6876:"The employment of leukotriene antagonists in cutaneous diseases belonging to allergological field" 3534: 2986: 2400: 2191: 1934: 1632: 1191: 1086: 3712:

Recent data in 2024 has emerged that neuronal integrity breakdown was reduced by ω−3 treatment in

2938: 1760: 1713: 1210: 1177: 471:

E; EPA-derived hydroxy metabolites have five ('penta' or 'P') double bonds (e.g. 5-hydroxy-eicosa

250: 3543:

The epoxy eicosatrienoic acids (or EETs)—and, presumably, the epoxy eicosatetraenoic acids—have

4198: 3892:

showed that aspirin and similar drugs inhibit prostaglandin synthesis. Von Euler received the

3784: 3719: 3671: 3632: 3580: 3009: 2575: 2522: 1195: 554:

isomeric products can exhibit dramatically different biological activities. Failing to specify

546:-HETE is 5-HETE). Nonetheless, certain eicosanoid-forming pathways do form R isomers and their 7849:"The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution" 5807: 5224:"Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice" 4477:"Is there a role for topically delivered eicosapentaenoic acid in the treatment of psoriasis?" 3738:

In general, the eicosanoids derived from AA promote inflammation, and those from EPA and from

2645:

studies needed to determine if inhibiting its production or action inhibits allergic reactons

141:

There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins,

9306: 9100: 8998: 8753: 5759:

Wittwer, J; Hersberger, M (2007). "The two faces of the 15-lipoxygenase in atherosclerosis".

4508: 3763:—Dietary ω−3 decreases tissue concentrations of AA, so there is less to form ω−6 eicosanoids. 3691: 3679: 3639: 2566: 2429: 2413: 2035: 1621: 1531: 1443: 1374: 968: 301: 28: 7523: 6733:

Bäck M, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE (2011).

2726:

antagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions

2699:

antagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions

126:

agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as

9333: 8611: 8526: 8302: 8247: 7722: 7370: 7064:

Qu Q, Xuan W, Fan GH (2015). "Roles of resolvins in the resolution of acute inflammation".

6386: 4078: 3932:"Eicosanoid Synthesis and Metabolism: Prostaglandins, Thromboxanes, Leukotrienes, Lipoxins" 3873: 3739: 3683: 3667: 2982: 2583: 2535: 2070: 2016: 1185: 884: 75: 7986: 7662:"Specialized pro-resolving mediators: endogenous regulators of infection and inflammation" 3391:

class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. In a

1330:

act specifically on phospholipids that contain AA, EPA or GPLA at their SN2 position. cPLA

8: 9043: 7825: 6375:"Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration" 6108: 4710: 4453: 3931: 3909: 3885: 3160: 3111: 3036: 2843: 1392:

initiate or contribute to the initiation of the catalysis of fatty acids to eicosanoids:

123: 119: 8094: 7726: 7374: 6874:

Nettis E, D'Erasmo M, Di Leo E, Calogiuri G, Montinaro V, Ferrannini A, Vacca A (2010).

6390: 4082: 3678:. There is 'B' level evidence ('good scientific evidence') for increased dietary ω−3 in 1925:

is the parent prostanoid to all other prostanoids. It is metabolized by (see diagram in

8521: 8347: 8342: 8337: 8222: 8077: 7873: 7848: 7794: 7745: 7710: 7686: 7661: 7639: 7596: 7553: 7503: 7314: 7285: 7260: 7236: 7211: 7187: 7162: 7135: 7108: 7089: 7046: 6953: 6926: 6902: 6875: 6856: 6808: 6783: 6764: 6671: 6608: 6575: 6556: 6513: 6470: 6407: 6374: 6309: 6284: 6265: 6207: 6182: 6158: 6131: 6077: 6034: 5912: 5887: 5858: 5833: 5736: 5711: 5687: 5662: 5638: 5613: 5518: 5493: 5436: 5388: 5363: 5296: 5164: 5139: 5112: 5087: 5029: 4862: 4678: 4417: 4390: 4297: 4048: 4006: 3979: 3293:, are potent bronchoconstrictors, increasers of vascular permeability in postcapillary 3013: 2296: 1716:(ROS) and the initial products in eicosanoid generation are themselves highly reactive 1170:

are non-enzymatically formed derivatives of polyunsaturated fatty acids that possess a

242: 8135: 8118: 7948: 7456: 5248: 5223: 4831: 4174: 4149: 4043: 4030: 3747: 2749:

thought to contribute to asthma as well as other allergic and allergic-like reactions

1522:(12-LOX or ALOX12) initiates the metabolism of arachidonic acid to 12-HpETE, 12-HETE, 1231:

involve the same enzymatic pathways that make their arachidonic acid-derived analogs.

8202: 8167: 8163: 8099: 8081: 8061: 7990: 7952: 7917: 7878: 7829: 7786: 7750: 7691: 7631: 7627: 7588: 7545: 7495: 7460: 7425: 7386: 7343: 7290: 7241: 7192: 7140: 7081: 7038: 6998: 6958: 6907: 6848: 6813: 6756: 6715: 6663: 6613: 6595: 6548: 6505: 6462: 6412: 6352: 6348: 6314: 6257: 6212: 6163: 6112: 6069: 6026: 5990: 5986: 5952: 5917: 5863: 5811: 5776: 5741: 5692: 5643: 5629: 5594: 5558: 5523: 5474: 5440: 5428: 5393: 5337: 5288: 5253: 5204: 5169: 5117: 5021: 4979: 4938: 4897: 4854: 4812: 4808: 4777: 4750: 4714: 4670: 4635: 4599: 4551: 4496: 4457: 4422: 4371: 4367: 4335: 4289: 4284: 4267: 4179: 4094: 4011: 3897: 3803:— are released quickly after the injury. The site may momentarily turn pale. Then TXA 3698: 2110: 1894: 1382: 1378: 7897: 7798: 7643: 7600: 7557: 7507: 7406:"Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease" 7093: 6860: 6675: 6560: 6517: 6474: 6269: 6081: 4682: 4301: 4052: 3881: 3864:

In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized

989: 9297: 9277: 9257: 9249: 9200: 9133: 9094: 9049: 8742: 8731: 8709: 8683: 8648: 8365: 8194: 8159: 8130: 8089: 8073: 7982: 7973:

Fritsche, Kevin (August 2006). "Fatty Acids as Modulators of the Immune Response".

7944: 7909: 7898:"Omega-3 polyunsaturated fatty acids and oxygenated metabolism in atherothrombosis" 7868: 7860: 7821: 7778: 7740: 7730: 7681: 7673: 7623: 7580: 7535: 7487: 7452: 7417: 7378: 7335: 7280: 7272: 7231: 7223: 7182: 7174: 7130: 7120: 7073: 7050: 7030: 6990: 6948: 6938: 6897: 6887: 6840: 6803: 6795: 6768: 6746: 6705: 6655: 6647: 6603: 6591: 6587: 6540: 6497: 6454: 6446: 6402: 6394: 6344: 6304: 6296: 6247: 6239: 6202: 6198: 6194: 6153: 6143: 6104: 6061: 6038: 6018: 5982: 5944: 5907: 5899: 5853: 5845: 5803: 5768: 5731: 5723: 5682: 5674: 5633: 5625: 5586: 5550: 5513: 5505: 5466: 5420: 5383: 5375: 5327: 5300: 5280: 5243: 5235: 5196: 5159: 5151: 5107: 5099: 5033: 5013: 4969: 4928: 4889: 4846: 4830:

Behrendt H, Kasche A, Ebner von Eschenbach C, Risse U, Huss-Marp J, Ring J (2001).

4804: 4742: 4706: 4662: 4627: 4589: 4541: 4488: 4449: 4412: 4402: 4363: 4327: 4279: 4235: 4169: 4161: 4086: 4038: 4001: 3991: 3889: 3796: 3620: 3568: 3478: 3455: 2934: 2902: 2148: 2130: 1408: 1299: 1284: 1252: 1128: 562:

isomers can be misleading. Here, all hydroperoxy and hydroxy substituents have the

261: 218: 63: 55: 7309: 5712:"Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15)" 5678: 5509: 4090: 3896:

in medicine in 1970, which Samuelsson, Vane, and Bergström also received in 1982.

1283:, and even certain eicosanoids. The activated cells then mobilize enzymes, termed 389:

A particular eicosanoid is denoted by a four-character abbreviation, composed of:

8722: 8443: 8287: 8240: 7913: 7339: 6994: 6300: 5903: 5590: 5554: 5379: 5200: 5155: 5017: 4974: 4957: 4866: 4124: 3133: 2388: 2376: 2345: 1753: 1741: 1706: 1690: 1655: 1617: 1519: 1511: 1158:. Some of these isoPs have been shown to possess anti-inflammatory activity (see 492: 170: 91: 43: 7178: 7109:"Biological Roles of Resolvins and Related Substances in the Resolution of Pain" 5772: 4631: 4245: 4234:

Eicosanoids with different letters have placement of double-bonds and different

4221:

Prostacyclin—PGI—was previously classified as prostaglandin and retains its old

3795:—An insect's sting will trigger the classic inflammatory response. Short acting 3775:—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. 2124: 1602:(i.e. epidermis-type lipoxygenase 3 or eLOX3) metabolizes arachidonic acid to 12 9234: 9226: 9185: 9165: 9157: 9149: 9116: 9108: 9081: 9073: 9065: 9057: 8908: 8900: 8892: 8871: 8863: 8814: 8806: 8582: 8433: 7864: 7227: 6710: 6693: 6450: 5727: 4933: 4916: 4666: 3648: 3624: 3556: 2855:

Specialized pro-resolving mediators class of inflammatory reaction suppressors

2795:

Specialized pro-resolving mediators class of inflammatory reaction suppressors

2768:

Specialized pro-resolving mediators class of inflammatory reaction suppressors

2249:. After release from its parent cell, the glutamate and glycine residues of LTC 2199: 2172: 2171:. Alternately, ALOX5 uses its LTA synthase activity to act convert 5-HPETE to 2144: 2114: 1396: 1358: 1346:

Next, the free fatty acid is oxygenated along any of several pathways; see the

527:)-HETE, 5S-HETE, or 5(S)-HETE). Since eicosanoid-forming enzymes commonly make 207: 197: 115: 7491: 6844: 6651: 6544: 6022: 5948: 5888:"Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism" 5470: 4746: 3900:

received it in chemistry in 1990 largely for his synthesis of prostaglandins.

3458:. However, the clinical significance of eoxins has not yet been demonstrated. 1263:

Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma,

534:

products either with marked preference or essentially exclusively, the use of

9327: 8667: 8461: 8423: 8418: 8403: 8370: 8282: 8085: 6784:"Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7" 6599: 6501: 4407: 3877: 3865: 3350: 3137: 3130: 2921:. Inhibition of COX-1 and/or the inducible COX-2 isoforms is the hallmark of 2884: 2489: 2210: 1914: 1518:, 8,15-dihydroxyeicosatetraenoic acid (i.e. 8,15-DiHETE), and 15-oxo-ETE and 1416: 1280: 1248: 1184:

or dopamine that are esterified to polyunsaturated fatty acids that activate

975: 903:

5-HEPE, 12-HEPE, 15-HEPE, and 20-HETE; LTA5, LTB5, LTC5, LTD5, and LTE5 (see

708: 433:

or PGG2) while their AA-derived leukotrienes have four double bonds (e.g. LTB

422:

or PGG3) while leukotrienes derived from EPA have five double bonds (e.g. LTB

412: 332:

double bonds, each located between carbons 5-6, 8-9, 11-12, 14-15, and 17-18.

127: 7735: 7382: 6943: 5832:

Yang, L; Mäki-Petäjä, K; Cheriyan, J; McEniery, C; Wilkinson, I. B. (2015).

5424: 4476: 3627:

controlling a wide array of cellular functions, especially those regulating

3250:(which, like 5-oxo-eicosatetraenoic acid, acts through the OXER1 receptor), 9208: 9141: 9127: 8774: 8551: 8513: 8476: 8471: 8438: 8428: 8375: 8198: 8171: 8103: 7994: 7956: 7921: 7882: 7833: 7790: 7754: 7695: 7635: 7592: 7549: 7499: 7464: 7429: 7347: 7294: 7245: 7196: 7144: 7085: 7042: 7002: 6962: 6911: 6852: 6817: 6760: 6719: 6667: 6617: 6552: 6509: 6466: 6416: 6356: 6318: 6261: 6216: 6167: 6116: 6073: 6030: 5994: 5956: 5921: 5867: 5815: 5780: 5745: 5696: 5647: 5598: 5562: 5527: 5478: 5432: 5397: 5341: 5332: 5315: 5292: 5257: 5208: 5173: 5121: 5025: 4983: 4942: 4901: 4893: 4858: 4781: 4754: 4718: 4674: 4639: 4603: 4555: 4500: 4461: 4426: 4375: 4339: 4183: 4098: 4015: 3833: 3808: 3675: 3628: 3584: 3544: 3060: 2906: 2898: 2888: 2866: 2579: 2553: 2225:). Either of the latter two enzymes act to attach the sulfur of cysteine's 1902: 1737: 1480: 1424: 1354: 1303: 1240: 1181: 769: 271: 174: 162: 79: 8206: 7902: