Eicosanoid

Pathways in biosynthesis of eicosanoids from arachidonic acid: there are parallel paths from EPA & DGLA.

In biochemistry, eicosanoids (preferred IUPAC name icosanoids) are signaling molecules made by oxidation of 20-carbon fatty acids. They exert complex control over many bodily systems; mainly in growth during and after physical activity, inflammation or immunity after the intake of toxic compounds and pathogens, and as messengers in the central nervous system. Many are classified as hormones. The networks of controls that depend upon eicosanoids are among the most complex in the human body.

Eicosanoids are derived from either omega-3 (ω-3) or omega-6 (ω-6) fatty acids. In general, the ω-6 eicosanoids are pro-inflammatory; ω-3s are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis.

There are multiple subfamilies of eicosanoids, including the prostaglandins, thromboxanes, and leukotrienes, as well as the lipoxins and eoxins, and others. For each, there are two or three separate series, derived from either an ω-3 or an ω-6 EFA. These series' different activities largely explain the health effects of ω-3 and ω-6 fats.

Nomenclature

See related detail at Essential Fatty Acid Interactions—Nomenclature

"Eicosanoid" (eicosa-, Greek for "twenty"; see icosahedron) is the collective term for oxygenated derivatives of three different 20-carbon fatty acids:

• Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds;
• Arachidonic acid (AA), an ω-6 fatty acid, with 4 double bonds;
• Dihomo-gamma-linolenic acid (DGLA), an ω-6, with 3 double bonds.

Current usage limits the term eicosanoid to leukotrienes (LT), eoxins (EX), and three types of prostanoids—prostaglandins (PG), prostacyclins (PGI) and thromboxanes (TX). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epi-lipoxins, epoxyeicosatrienoic acids (EETs) and endocannabinoids. LTs and prostanoids are sometimes termed 'classic eicosanoids' in contrast to the 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'.

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

• Its two-letter abbreviation (above),
• One A-B-C sequence-letter; and
• A subscript, indicating the number of double bonds.

Examples are:

• The EPA-derived prostanoids have three double bonds, (e.g., PGG₃, PGH₃, PGI₃, TXA₃) while its leukotrienes have five, (LTB₅).
• The AA-derived prostanoids have two double bonds, (e.g., PGG₂, PGH₂, PGI₂, TXA₂) while its leukotrienes have four, (LTB₄).

Furthermore, stereochemistry may differ among the pathways, indicated by Greek letters, e.g. for (PGF_2α).

Biosynthesis

Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids:

• Cyclooxygenase, or COX, generates the prostanoids from arachidonic acid.
• Lipoxygenase, or LOX, in several forms. 5-Lipoxygenase (5-LO) generates the leukotrienes from arachidonic acid and via transcellular biosynthesis is also involved in lipoxin generation. 15-Lipoxygenase generates the eoxins.

Eicosanoids are not stored within cells, but are synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane.

Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) This triggers the release of a phospholipase at the cell membrane. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by phospholipase A₂) or diacylglycerol (by phospholipase C). This frees a 20-carbon fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation.

The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A₂ (cPLA₂) is the key actor, as cells lacking cPLA₂ are, in general, devoid of eicosanoid synthesis. The phospholipase cPLA₂ is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA₂ may also release the lysophospholipid that becomes platelet-activating factor.

Peroxidation and reactive oxygen species

Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O₂). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidations proceed with high stereoselectivity (enzymatic oxidations are considered practically stereospecific).

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.
		200px
Prostacyclin I2. The second ring distinguishes it from the prostaglandins.		Leukotriene E4, an example of a cysteinyl leukotriene.

Prostanoid pathways

See Prostanoid#Biosynthesis.

Cyclooxygenase (COX) catalyzes the conversion of the free fatty acids to prostanoids by a two-step process. First, two molecules of O₂ are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more detail of these steps at Cyclooxygenase).

All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings. (See more detail, including the enzymes involved, in diagrams at Prostanoid.)

Several drugs lower inflammation by blocking prostanoid synthesis; see detail at Cyclooxygenase, Aspirin and NSAID.

Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways

See Leukotriene#Biosynthesis, Hydroxyeicosatetraenoic acid, and Eoxin#Human biosynthesis.

The enzyme 5-lipoxygenase (5-LO or ALOX5) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which if not further metabolized by the enzyme LTA synthase, is rapidly reduces to 5-hydroxyeicosatetraenoic acid (5-HETE) by ubiquitous cellular glutathione-dependent peroxidases. The enzyme LTA synthase acts on 5-HPETE to convert it into leukotriene A₄ (LTA₄), which may be converted into LTB₄ by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA₄ to make LTC₄, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD₄. The leukotriene LTD₄ is then cleaved by dipeptidases to make LTE₄. The leukotrienes LTC₄, LTD₄ and LTE₄ all contain cysteine and are collectively known as the cysteinyl leukotrienes.

The enzyme arachidonate 12-lipoxygenase (12-LO or ALOX12) metabolizes arachidonic acid to the S stereoisomer of 12-hydroperoxyeicosatetraenoic acid (5-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 12-hydroxyeicosatetraenoic acid (12-HETE) or further metabolized to hepoxilins (Hx) such as HxA3 and HxB.

The enzymes 15-lipoxygenase-1 (15-LO-1 or ALOX15) and 15-lipoxygenase-2 (15-LO-2, ALOX15B) metabolize arachidonic acid to the S stereoisomer of 15-Hydroperoxyeicosatetraenoic acid (15-HPETE) which is rapidly reduced by cellular peroxidases to the S stereoisomer of 15-Hydroxyicosatetraenoic acid (15-HETE).

A subset of Cytochrome P450 (CYP450) microsome-bound ω-hydroxylases (see 20-Hydroxyeicosatetraenoic acid) metabolize arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) and 19-hydroxyeicosatetraenoic acid by an omega oxidation reaction.

Function and pharmacology

Metabolic actions of selected prostanoids and leukotrienes^†

PGD2	Promotion of sleep	TXA2	Stimulation of platelet aggregation; vasoconstriction
PGE2	Smooth muscle contraction; inducing pain, heat, fever; bronchoconstriction	15d-PGJ2	Adipocyte differentiation
PGF2α	Uterine contraction	LTB4	Leukocyte chemotaxis
PGI2	Inhibition of platelet aggregation; vasodilation; embryo implantation	Cysteinyl-LTs	Anaphylaxis; bronchial smooth muscle contraction.
†Shown eicosanoids are AA-derived; in general, EPA-derived have weaker activity

Eicosanoids exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. They are found in most living things. In humans, eicosanoids are local hormones that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated.

Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes. Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors.

Receptors: There are specific receptors for all eicosanoids (see also: eicosanoid receptors)

Leukotrienes: CysLT1 (Cysteinyl leukotriene receptor type 1) CysLT2 (Cysteinyl leukotriene receptor type 2) BLT1 (Leukotriene B4 receptor)

Prostanoids: PGD2: DP-(PGD2) PGE2: EP1-(PGE2) EP2-(PGE2) EP3-(PGE2) EP4-(PGE2) PGF2α: FP-(PGF2α) PGI2 (prostacyclin): IP-(PGI2) TXA2 (thromboxane): TP-(TXA2)

The ω-3 and ω-6 series

Main article: Essential fatty acid interactions

The reduction in AA-derived eicosanoids and the diminished activity of the alternative products generated from ω-3 fatty acids serve as the foundation for explaining some of the beneficial effects of greater ω-3 intake.

— Kevin Fritsche, Fatty Acids as Modulators of the Immune Response

Arachidonic acid (AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'—more than twenty different eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity and the central nervous system.

In the inflammatory response, two other groups of dietary fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3) provides the most important competing cascade. DGLA (20:3 ω-6) provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory fatty acids, especially the ω-3s, has been linked to several inflammation-related diseases, and perhaps some mental illnesses.

The U.S. National Institutes of Health and the National Library of Medicine state that there is 'A' level evidence that increased dietary ω-3 improves outcomes in hypertriglyceridemia, secondary cardiovascular disease prevention and hypertension. There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in primary prevention of cardiovascular disease, rheumatoid arthritis and protection from ciclosporin toxicity in organ transplant patients. They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.

Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter membrane composition and function, including the composition of lipid rafts; (b) change cytokine biosynthesis and (c) directly activate gene transcription. Of these, the action on eicosanoids is the best explored.

Mechanisms of ω-3 action

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.

Pharmacy: Eicosanoid, eicosanoid analogs and receptor agonists/antagonists used as medicines

Medicine	Type	Medical condition or use
Alprostadil	PGE1	Erectile dysfunction, maintaining a patent ductus arteriosus in the fetus
Beraprost	PGI1 analog	Pulmonary hypertension, avoiding reperfusion injury
Bimatoprost	PGF2α analog	Glaucoma, ocular hypertension
Carboprost	PGF2α analog	Labor induction, abortifacient in early pregnancy
Dinoprostone	PGE2	Labor induction
Iloprost	PGI2 analog	Pulmonary arterial hypertension
Latanoprost	PGF2α analog	Glaucoma, ocular hypertension
Misoprostol	PGE1 analog	Stomach ulcers, labor induction, abortifacient
Montelukast	LT receptor antagonist	Asthma, seasonal allergies
Travoprost	PGF2α analog	Glaucoma, ocular hypertension
Treprostinil	PGI analog	Pulmonary hypertension
U46619	Longer lived TX analog	Research only
Zafirlukast	LT receptor antagonist	Asthma

Action of prostanoids

Main articles: Prostaglandin, Prostacyclin and Thromboxane

Prostanoids mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain and fever. Inhibition of cyclooxygenase, specifically the inducible COX-2 isoform, is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. COX-2 is responsible for pain and inflammation, while COX-1 is responsible for platelet clotting actions.

Prostanoids activate the PPAR_γ members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription.

Action of leukotrienes

Main article: Leukotriene

Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC₄ in luteinizing hormone secretion. LTB₄ causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. Blocking leukotriene receptors can play a role in the management of inflammatory diseases such as asthma (by the drugs montelukast and zafirlukast), psoriasis, and rheumatoid arthritis.

The slow reacting substance of anaphylaxis comprises the cysteinyl leukotrienes. These have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in atherosclerosis and inflammatory gastrointestinal diseases. They are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in immediate hypersensitivity reactions. Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.

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.

External links

• Eicosanoids at the US National Library of Medicine Medical Subject Headings (MeSH)