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Eicosanoids are
signaling molecules In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...
made by the
enzymatic An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...
or non-enzymatic
oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
of
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
or other
polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
s (PUFAs) that are, similar to
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
, around 20 carbon units in length. Eicosanoids are a sub-category of
oxylipin Oxylipins constitute a family of oxygenated natural products which are formed from fatty acids by pathways involving at least one step of dioxygen-dependent oxidation. These small polar lipid compounds are metabolites of polyunsaturated fatty aci ...
s, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as
cell signal In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryo ...
ing molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
,
allergy Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
,
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
and other
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
s; regulating the
abortion Abortion is the early termination of a pregnancy by removal or expulsion of an embryo or fetus. Abortions that occur without intervention are known as miscarriages or "spontaneous abortions", and occur in roughly 30–40% of all pregnan ...
of
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
and normal
childbirth Childbirth, also known as labour, parturition and delivery, is the completion of pregnancy, where one or more Fetus, fetuses exits the Womb, internal environment of the mother via vaginal delivery or caesarean section and becomes a newborn to ...
; contributing to the perception of
pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
; regulating
cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
; controlling
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as
autocrine signaling Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with ...
agents to impact their cells of origin or as
paracrine signaling In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as parac ...
agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as
prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...
s, may also have
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
roles as
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s to influence the function of distant cells. There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins,
thromboxane Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring. Thromboxane is named for ...
s,
leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ...
s,
lipoxin A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvi ...
s,
resolvin Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one ...
s, and
eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...
s. 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
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and
allergy Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
reactions,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
,
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
, cancer growth, and a host of other processes.


Nomenclature


Fatty acid sources

"Eicosanoid" () is the collective term for
straight-chain In chemistry, an open-chain compound (or open chain compound) or acyclic compound (Greek prefix ''α'' 'without' and ''κύκλος'' 'cycle') is a compound with a linear structure, rather than a cyclic one. An open-chain compound having no side ...
PUFAs (
polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
s) of 20 carbon units in length that have been metabolized or otherwise converted to oxygen-containing products. The PUFA precursors to the eicosanoids include: *
Arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
(AA), i.e. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid is an ω−6 fatty acid with four
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s in the ''cis'' configuration (denoted ''Z'' in
E–Z notation ''E''–''Z'' configuration, or the ''E''–''Z'' convention, is the IUPAC preferred method of describing the absolute stereochemistry of double bonds in organic chemistry. It is an extension of ''cis''–''trans'' isomer notation (which o ...
), each located between carbons 5-6, 8-9, 11-12, and 14-15 (see carbon numbering). * Adrenic acid (AdA), i.e. 7''Z'',10''Z'',13''Z'',16''Z''-docosatetraenoic acid, is an ω−6 fatty acid with four ''cis'' double bonds, each located between carbons 7-8, 10-11, 13-14, and 16-17. *
Eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...
(EPA), i.e. 5''Z'',8''Z'',11''Z'',14''Z'',17''Z''-eicosapentaenoic acid is an ω−3 fatty acid with five ''cis'' double bonds, each located between carbons 5-6, 8-9, 11-12, 14-15, and 17-18. * Dihomo-gamma-linolenic acid (DGLA), i.e. 8''Z'',11''Z'',14''Z''-eicosatrienoic acid is an ω−6 fatty acid with three ''cis'' double bonds, each located between carbons 8-9, 11-12, and 14-15. *
Mead acid Mead acid is an omega-9 fatty acid, first characterized by James F. Mead. As with some other omega-9 polyunsaturated fatty acids, animals can make Mead acid ''de novo''. Its elevated presence in the blood is an indication of essential fatty ac ...
, i.e. 5''Z'',8''Z'',11''Z''-eicosatrienoic acid, is an ω−9 fatty acid containing three ''cis'' double bonds, each located between carbons 5-6, 8-9, and 11-12.


Abbreviation

A particular eicosanoid is denoted by a four-character abbreviation, composed of: *its two-letter abbreviation (LT, EX or PG, as described below), *one A-B-C sequence-letter,Eicosanoids with different letters have placement of double-bonds and different
functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
s attached to the molecular skeleton. Letters indicate roughly the order the eicosanoids were first described in the literature. For diagrams for PG –Hsee
*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 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-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 Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...
of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters (e.g. PGF versus PGF). For hydroperoxy and hydroxy eicosanoids an ''S'' or ''R'' designates the
chirality Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable fro ...
of their substituents (e.g. 5''S''-hydroxy-eicosateteraenoic acid lso termed 5(''S'')-, 5S-hydroxy-, and 5(S)-hydroxy-eicosatetraenoic acidis given the trivial names of 5''S''-HETE, 5(''S'')-HETE, 5S-HETE, or 5(S)-HETE). Since eicosanoid-forming enzymes commonly make ''S''
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...
products either with marked preference or essentially exclusively, the use of ''S''/''R'' designations has often been dropped (e.g. 5''S''-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.


Classic eicosanoids

Current usage limits the term eicosanoid to: *ω−6 series eicosanoids derived from arachidonic acid: ** Hydroxyeicosatetraenoic acids (HETE) include the following metabolites of arachidonic acid: ***
5-HETE 5-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(' ...
, 12-HETE,
15-hydroxyeicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S' ...
(i.e. 15-HETE), 20-hydroxyeicosatetraenoic acid (i.e. 20-HETE), and 19-HETE. **
Leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ...
s (LT) include the following metabolites of arachidonic acid: *** LTA4, LTB44, LTC4, LTD4, and LTE4. **
Eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...
s (EX) include the following metabolites of arachidnoic acid: *** EXA4, EXC4, EXD4, and EXE4. **
Prostanoid In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes ...
s consisting of several different types: ***
Prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...
s (PG) include the following metabolites of arachidonic acid: **** PGG2, PGH2, PGE2, PGD2, PGF, PGA2, PGB2 (see ). ***
Prostacyclin Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosteno ...
s include: **** PGI2. ***
Thromboxane Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring. Thromboxane is named for ...
s (TX) include the following metabolites of arachidonic acid: **** TXA2 and TXB2. *** Cyclopentenone prostaglandins include the following metabolites of arachidonic acid: ****PGA1, PGA2 (see
Prostanoid In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes ...
, 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 bond between carbons 5 and 6 and therefore have 1 less double bond than their arachidonic acid-derived analogs. They are the following: **PGA1, PGE1, and TXA1. *ω−3 series eicosanoids: **
Resolvin Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one ...
s of the E series (RvE) (D series resolvins vDare metabolites of the 22-carbon ω−3 fatty acid
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...
; see ). RvE include the following metabolites of eicosapentaenoic acid: ***RvE1, 18S-RvE1, RvE2, and RvE3. **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): ***5-HEPE, 12-HEPE, 15-HEPE, and 20-HETE; LTA5, LTB5, LTC5, LTD5, and LTE5 (see ); PGE3, PGD3, PGF, and Δ(17)-6-keto PGF; PGI3 (see ); and TXA3 and TXB3. *ω−9 series eicosanoids **Hydroxy are derived form mead acid, is metabolized to the 3 double bond-containing analog of 5-HETE viz., 5-HETrE (see ). 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 eicosanoid Nonclassic eicosanoids are biologically active signaling molecules made by oxygenation of twenty-carbon fatty acids other than the classic eicosanoids. Terminology : "Eicosanoid" is the collective term for oxygenated derivatives of three differ ...
s'. These included the following classes: *
Oxoeicosanoid The oxoeicosanoids are nonclassic eicosanoids, derived from arachidonic acid (AA). For example, Lipoxygenase produces 5-HETE from AA; a dehydrogenase then produces 5-oxo-eicosatetraenoic acid, an oxoeicosanoid, from 5-HETE. They are similar ...
s (oxo-ETE) include the following metabolites: ** 5-Oxo-eicosatetraenoic acid (5-oxo-ETE), 12-oxo-ETE (see ), and 15-oxo-ETE, which are metabolites of arachidonic acid (see
15-Hydroxyeicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S' ...
) and 5-oxo-ETrE which is a metabolite of mead acid (see ). *
Hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoi ...
s (Hx) include the following arachidonic acid metabolites: ** HxA3 and HxB3. *
Lipoxin A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvi ...
s (Lx) include the following metabolites of arachidonic acid: ** LxA4 and LxB4 (see
Specialized pro-resolving mediators Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
). *
Epi-lipoxin Epi-lipoxins are trihydroxy (i.e. containing 3 hydroxyl residues) metabolites of arachidonic acid. They are 15''R''-epimers of their lipoxin counterparts; that is, the epi-lipoxins, 15-epi-lipoxin A4 (15-epi-LxA4) and 15-epi-lipoxin B4 (15-epi-L ...
s (epi-Lx) include the following metabolites of arachidonic acid: ** 15-epi-LxA4 (also termed AT-LxA4) and 15-epi-LxB4 (also termed AT-LxB4). *
Epoxyeicosatrienoic acid The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic e ...
s (EET) include the following metabolites of arachidonic acid: **5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. *
Epoxyeicosatetraenoic acid Epoxyeicosatetraenoic acids (EEQs or EpETEs) are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenase ...
s (EEQ) include the following metabolites of eicosapentaenoic acid: **5,6-EEQ, 8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 15,16-EEQ. *
Isoprostane The isoprostanes are prostaglandin-like compounds formed ''in vivo'' from the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase (COX) enzymes. These nonclassi ...
s (isoP) are non-enzymatically formed derivatives of
polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
s studied as markers of
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
; they include the following arachidonic acid-derived isoPs which are named based on their structural similarities to PGs: **D2-isoPs, E2-isoPs, A2-isoPs, and J2-isoPs; and two epoxide-containing isoPs, 5,6-epoxyisoprostane E2 and 5,6-epoxyisoprostane A2. Some of these isoPs have been shown to possess anti-inflammatory activity (see ). *
Isofuran Isofurans are a family of organic compounds termed nonclassic eicosanoids. They arise nonenzymatically by free radical peroxidation of arachidonic acid. The isofurans are similar to the isoprostanes and are formed under similar conditions, but c ...
s are non-enzymatically formed derivatives of polyunsaturated fatty acids that possess a
furan Furan is a Heterocyclic compound, heterocyclic organic compound, consisting of a five-membered aromatic Ring (chemistry), ring with four carbon Atom, atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as f ...
ring structure; they are studied as markers of oxidative stress. There are 256 potentially different furan ring-containing isomers that can be derived from arachidonic acid. *
Endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
are certain
glycerolipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...
s or dopamine that are esterified to polyunsaturated fatty acids that activate
cannabinoid receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cann ...
s. They include the following arachidonic acid-esterified agents: **
Arachidonoylethanolamine Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...
,
2-arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is pres ...
, 2-arachidonyl glyceryl ether, ''O''-arachidonoyl-ethanolamine, and ''N''-arachidonoyl dopamine. 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.


Biosynthesis

Eicosanoids typically are not stored within cells but rather synthesized as required. They derive from the
fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
s that make up the
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
and
nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer polar membrane, membranes that in eukaryotic cells surround the Cell nucleus, nucleus, which encloses the genome, genetic material. The nuclear envelope con ...
. 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 Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
, other physical perturbations, attack by
pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
s, or stimuli made by nearby cells, tissues, or pathogens such as
chemotactic factor Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
s,
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s,
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
s, and even certain eicosanoids. The activated cells then mobilize enzymes, termed phospholipases A2 (PLA2), capable of releasing ω−6 and ω−3 fatty acids from membrane storage. These fatty acids are bound in
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
linkage to the SN2 position of membrane
phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s; PLA2 act as
esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...
s to release the fatty acid. There are several classes of PLA2 with type IV cytosolic PLA2 (cPLA2) appearing to be responsible for releasing the fatty acids under many conditions of cell activation. The cPLA2 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 Platelet-activating factor, also known as PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation and degranulation, inflammation, and an ...
.


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 Lipoxygenases () (LOX) are a family of (non- heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into ce ...
or
COX Cox or COX may refer to: Companies * Cox Enterprises, a media and communications company ** Cox Communications, cable provider ** Cox Media Group, a company that owns television and radio stations ** Cox Automotive, an Atlanta-based busines ...
) add
molecular oxygen There are several known allotropes of oxygen. The most familiar is molecular oxygen (), present at significant levels in Earth's atmosphere and also known as dioxygen or triplet oxygen. Another is the highly reactive ozone (). Others are: * Atomic ...
(O2). Although the fatty acid is
symmetric Symmetry () in everyday life refers to a sense of harmonious and beautiful proportion and balance. In mathematics, the term has a more precise definition and is usually used to refer to an object that is invariant under some transformations ...
, the resulting eicosanoids are
chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...
; the oxidations proceed with high
stereoselectivity In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation ...
(enzymatic oxidations are considered practically stereospecific). Four families of
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s initiate or contribute to the initiation of the catalysis of fatty acids to eicosanoids: *
Cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...
s (COXs):
COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 ( HUGO PTGS1), is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of three cyclooxygenases. History Cyclooxygenase (COX) is the centr ...
and
COX-2 Cyclooxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2), is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachid ...
initiate the metabolism of
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
to
prostanoid In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes ...
s that contain two double bonds, i.e. the
prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...
s (e.g. PGE2),
prostacyclin Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosteno ...
s (i.e. PGI2), and
thromboxane Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring. Thromboxane is named for ...
s (e.g. TXA2). The two COX enzymes likewise initiate the metabolism of: a)
Eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...
, 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. PGE3, PGI3, and TXA3 and b) Dihomo-γ-linolenic acid, which has three double bonds, to prostanoid, prostacyclin, and thromboxane products that have only one double bond, e.g. PGE1, PGI1, and TXA1. *
Lipoxygenase Lipoxygenases () (LOX) are a family of (non- heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into ce ...
s (LOXs):
5-Lipoxygenase Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...
(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-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(' ...
(5-HETE) or further metabolized to the
leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ...
s (e.g. LTB4 and LTC4); 5-HETE may be oxidized to 5-oxo-eicosatetraenoic acid (5-oxo-ETE). In similar fashions,
15-lipoxygenase ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The ...
(15-lipoxygenase 1, 15-LOX, 15-LOX1, or ALOX15) initiates the metabolism of arachidonic acid to 15-HpETE, 15-HETE,
eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...
s, 8,15-dihydroxyeicosatetraenoic acid (i.e. 8,15-DiHETE), and 15-oxo-ETE and
12-lipoxygenase ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on ...
(12-LOX or ALOX12) initiates the metabolism of arachidonic acid to 12-HpETE, 12-HETE,
hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoi ...
s, and 12-oxo-ETE. These enzymes also initiate the metabolism of; a)
Eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...
to analogs of the arachidonic acid metabolites that contain 5 rather than four double bonds, e.g. 5-hydroxyeicosapentaenoic 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 ''S''
chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...
configuration and are more properly termed 5''S''-HpETE, 5''S''-HETE, 12''S''-HpETE, 12''S''-HETE, 15''S''-HpETE and, 15''S''-HETE.
ALOX12B Arachidonate 12-lipoxygenase, 12R type, also known as ALOX12B, 12''R''-LOX, and arachidonate lipoxygenase 3, is a lipoxygenase-type enzyme composed of 701 amino acids and encoded by the ''ALOX12B'' gene. The gene is located on chromosome 17 at po ...
(i.e. arachidonate 12-lipoxygenase, 12R type) forms ''R'' chirality products, i.e. 12''R''-HpETE and 12''R''-HETE. Similarly,
ALOXE3 Epidermis-type lipoxygenase 3 (ALOXE3 or eLOX3) is a member of the lipoxygenase family of enzymes; in humans, it is encoded by the ''ALOXE3'' gene. This gene is located on chromosome 17 at position 13.1 where it forms a cluster with two other lip ...
(i.e. epidermis-type lipoxygenase 3 or eLOX3) metabolizes arachidonic acid to 12''R''-HpETE and 12''R''-HETE; however these are minor products that this enzyme forms only under a limited set of conditions. ALOXE3 preferentially metabolizes arachidonic acid to hepoxilins. *
Epoxygenase Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP450 or just CYP) enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities. The most thoroughly-studi ...
s: these are
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzymes which generate
nonclassic eicosanoid Nonclassic eicosanoids are biologically active signaling molecules made by oxygenation of twenty-carbon fatty acids other than the classic eicosanoids. Terminology : "Eicosanoid" is the collective term for oxygenated derivatives of three differ ...
epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...
s 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 The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic e ...
); 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 Epoxyeicosatetraenoic acids (EEQs or EpETEs) are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenase ...
); c) Dihomo-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. *
Cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
microsome In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, l ...
ω hydroxylases:
CYP4A11 Cytochrome P450 4A11 is a protein that in humans is codified by the ''CYP4A11'' gene. Family This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases, catalyzing many reactions i ...
, CYP4A22,
CYP4F2 Cytochrome P450 4F2 is a protein that in humans is encoded by the ''CYP4F2'' gene. This protein is an enzyme, a type of protein that catalyzes (helps speed up) chemical reactions inside cells. This specific enzyme is part of the superfamily of ...
, and
CYP4F3 Cytochrome P450 4F3, also leukotriene-B(4) omega-hydroxylase 2, is an enzyme that in humans is encoded by the ''CYP4F3'' gene. ''CYP4F3'' encodes two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single ...
metabolize arachidonic acid primarily to 20-hydroxyeicosatetraenoic acid (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. 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
lipoxin A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvi ...
s and with
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series
resolvin Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one ...
s (RvEs) (see
Specialized pro-resolving mediators Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
). 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
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s. Oxidation by either COX or lipoxygenase releases
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) and the initial products in eicosanoid generation are themselves highly reactive
peroxide In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...
s. LTA4 can form
adduct In chemistry, an adduct (; alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components. The resultant is ...
s with tissue
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
. Other reactions of lipoxygenases generate cellular damage;
murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
models implicate 15-lipoxygenase in the
pathogenesis In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes . Descript ...
of
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
. 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
hydrolase In biochemistry, hydrolases constitute a class of enzymes that commonly function as biochemical catalysts that use water to break a chemical bond: :\ce \quad \xrightarrowtext\quad \ce This typically results in dividing a larger molecule into s ...
s, and
carrier protein A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they ...
s) 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 Transcription is the process of copying a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transc ...
there; LTB4 is ligand for
PPARα Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gen ...
. ''(See diagram at PPAR.)''


Prostanoid pathways

Both COX1 and COX2 (also termed prostaglandin-endoperoxide synthase-1 (
PTGS1 Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 ( HUGO PTGS1), is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of three cyclooxygenases. History Cyclooxygenase (COX) is the centr ...
) and
PTGS2 Cyclooxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2), is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachid ...
, respectively) metabolize arachidonic acid by adding molecular O2 between carbons 9 and 11 to form an
endoperoxide In organic chemistry, organic peroxides are organic compounds containing the peroxide functional group (). If the R′ is hydrogen, the compounds are called hydroperoxides, which are discussed in that article. The O−O bond of peroxides easily b ...
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 Cyclopentane (also called C pentane) is a highly flammable alicyclic compound, alicyclic hydrocarbon with chemical formula C5H10, C5H10 and CAS number 287-92-3, consisting of a ring of five carbon atoms each bonded with two hydrogen atoms above and ...
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 In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
residue thereby forming PGH2. PGH2 is the parent prostanoid to all other prostanoids. It is metabolized by (see diagram in
Prostanoid In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes ...
): a) The
prostaglandin E synthase Prostaglandin E synthase (, or PGE synthase) is an enzyme involved in eicosanoid and glutathione metabolism, a member of MAPEG family. It generates prostaglandin E (PGE) from prostaglandin H2. The synthase generating PGE2 is a membrane-associate ...
pathway in which any one of three
isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...
s,
PTGES Microsomal prostaglandin E synthase-1 (mPGES-1) or Prostaglandin E synthase is an enzyme that in humans is encoded by the ''PTGES'' gene. The protein encoded by this gene is a glutathione-dependent prostaglandin E synthase. The expression of thi ...
,
PTGES2 Microsomal prostaglandin E synthase-2 (mPGES-2) or Prostaglandin E synthase 2 is an enzyme that in humans encoded by the ''PTGES2'' gene located on chromosome 9. The protein encoded by this gene is a membrane-associated prostaglandin E synthase, ...
, or
PTGES3 Prostaglandin E synthase 3 (cytosolic) is a Prostaglandin E synthase enzyme that in humans is encoded by the PTGES3 gene. The protein encoded by this gene is also known as p23 which functions as a chaperone which is required for proper functio ...
, convert PGH2 to PGE2 (subsequent products of this pathway include PGA2 and PGB2 (see ); b) PGF synthase which converts PGH2 to PGF; 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 Prostaglandin-I synthase () also known as prostaglandin I2 (prostacyclin) synthase (PTGIS) or CYP8A1 is an enzyme involved in prostanoid biosynthesis that in humans is encoded by the ''PTGIS'' gene. This enzyme belongs to the family of cytochrom ...
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 In chemistry, a dehydration reaction is a chemical reaction that involves the loss of an H2O from the reacting molecule(s) or ion(s). This reaction results in the release of the H2O as water. When the reaction involves the coupling of two molecu ...
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 In physical organic chemistry, a conjugated system is a system of connected p-orbitals with delocalized electrons in a molecule, which in general lowers the overall energy of the molecule and increases Chemical stability, stability. It is Reson ...
with a
carbonyl group In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such as aldehydes ...
that causes these PGs to form bonds with a diverse range of bioactive proteins (for more see the diagrams at
Prostanoid In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes ...
).


Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways

The enzyme
5-lipoxygenase Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...
(5-LO or ALOX5) converts
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
into
5-hydroperoxyeicosatetraenoic acid Arachidonic acid 5-hydroperoxide (5-hydroperoxyeicosatetraenoic acid, 5-HPETE) is an intermediate in the metabolism of arachidonic acid by the ALOX5 enzyme in humans or Alox5 enzyme in other mammals. The intermediate is then further metabolized to: ...
(5-HPETE), which may be released and rapidly reduced to
5-hydroxyeicosatetraenoic acid 5-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(' ...
(5-HETE) by ubiquitous cellular
glutathione Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
-dependent
peroxidase Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides, and should not be confused with other ...
s. Alternately, ALOX5 uses its LTA synthase activity to act convert 5-HPETE to leukotriene A4 (LTA4). LTA4 is then metabolized either to LTB4 by leukotriene A4 hydrolase or leukotriene C4 (LTC4) by either LTC4 synthase or microsomal
glutathione S-transferase Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryote, eukaryotic and prokaryote, prokaryotic Biotransformation#Phase II reaction, phase II metabolic isozymes best known for their ability to Catalysis, ...
2 (
MGST2 Microsomal glutathione S-transferase 2 is an enzyme that in humans is encoded by the ''MGST2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides ...
). Either of the latter two enzymes act to attach the sulfur of cysteine's
thio- The prefix thio-, when applied to a chemical, such as an ion, means that an oxygen atom in the compound has been replaced by a sulfur atom. This term is often used in organic chemistry. For example, from the word ''ether,'' referring to an oxy ...
(i.e. SH) group in the tripeptide
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
-
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
-
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
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 Gamma-glutamyltransferase (also γ-glutamyltransferase, GGT, gamma-GT, gamma-glutamyl transpeptidase; ) is a transferase (a type of enzyme) that catalyzes the transfer of gamma- glutamyl functional groups from molecules such as glutathion ...
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 (or glutathione S-transferase in cells;
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
s,
mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
s, and
alveolar Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit. Uses in anatomy and zoology * Pulmonary alveolus, an air sac in the lungs ** Alveolar cell or pneumocyte ** Alveolar duct ** Alveolar macrophage * M ...
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s possess relatively high levels of LTC4 synthase and accordingly form LTC4 rather than or to a far greater extent than LTB4. 5-LOX may also work in series with cytochrome P450 oxygenases or aspirin-treated COX2 to form Resolvins RvE1, RvE2, and 18S-RvE1 (see ). The enzyme
arachidonate 12-lipoxygenase ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on ...
(12-LO or ALOX12) metabolizes arachidonic acid to the ''S'' stereoisomer of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) which is rapidly reduced by cellular peroxidases to the ''S'' stereoisomer of
12-hydroxyeicosatetraenoic acid 12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5''Z'',''8Z'',10''E'',14''Z'' cis–trans configuration (Z=cis, E=trans) in ...
(12-HETE) or further metabolized to
hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoi ...
s (Hx) such as HxA3 and HxB. The enzymes
15-lipoxygenase ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The ...
-1 (15-LO-1 or
ALOX15 ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically import ...
) and 15-lipoxygenase-2 (15-LO-2,
ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Funct ...
) 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-hydroxyeicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S' ...
(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 ). A subset of
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
(CYP450)
microsome In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, l ...
-bound ω hydroxylases metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) and 19-hydroxyeicosatetraenoic acid by an
omega oxidation Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fa ...
reaction.


Epoxyeicosanoid pathway

The human cytochrome P450 (CYP) epoxygenases, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 metabolize arachidonic acid to the non-classic
epoxyeicosatrienoic acid The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic e ...
s (EETs) by converting one of the fatty acid's
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s to its
epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...
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 Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...
to five epoxide
epoxyeicosatetraenoic acid Epoxyeicosatetraenoic acids (EEQs or EpETEs) are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenase ...
s (EEQs) 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 (see
Cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...
) 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.


Prostanoids

Many of the prostanoids are known to mediate local symptoms of
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
:
vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...
or
vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...
,
coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...
,
pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
, and
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
. Inhibition of COX-1 and/or the inducible COX-2 isoforms is the hallmark of
NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s (non-steroidal anti-inflammatory drugs), such as
aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
. Prostanoids also activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, and directly influence
gene transcription Transcription is the process of copying a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transc ...
. 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.


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 Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
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-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(' ...
(which, like 5-oxo-eicosatetraenoic acid, acts through the OXER1 receptor), 5-oxo-eicosatetraenoic acid,
12-hydroxyeicosatetraenoic acid 12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5''Z'',''8Z'',10''E'',14''Z'' cis–trans configuration (Z=cis, E=trans) in ...
,
15-hydroxyeicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S' ...
, 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
venule A venule is a very small vein in the microcirculation that allows blood to return from the capillary beds to drain into the venous system via increasingly larger veins. Post-capillary venules are the smallest of the veins with a diameter of ...
s, and stimulators of
mucus Mucus (, ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both Serous fluid, serous and muc ...
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 Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) contribute ...
receptor viz.,
montelukast Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. ...
,
zafirlukast Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headaches and stomach upset often occur. Some rare side effects can occur, whic ...
, and pranlukast, are used clinically as maintenance treatment for allergen-induced
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
and
rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip. The inflammation is caused by viruses, bacteria, irritant ...
;
nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents bl ...
-induced asthma and rhinitis (see
aspirin-exacerbated respiratory disease Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's Triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic ...
); exercise- and cold-air induced asthma (see Exercise-induced bronchoconstriction); and childhood
sleep apnea Sleep apnea (sleep apnoea or sleep apnœa in British English) is a sleep-related breathing disorder in which repetitive Apnea, pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor vent ...
due to adenotonsillar hypertrophy (see ). When combined with
antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...
drug therapy, they also appear useful for treating
urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
l 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 Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. In a
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
, AT-LXA4 and a comparatively stable analog of LXB4, 15''R/S''-methyl-LXB4, reduced the severity of
eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
in a study of 60 infants and, in another study, inhaled LXA4 decreased LTC4-initiated bronchoprovocation in patients with asthma.


Eoxins

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–Sternberg cells cells has also led to suggestion that they are involved 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 (see
Phases of clinical research The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
) for the treatment of the inflammation-based
dry eye syndrome Dry eye syndrome, also known as keratoconjunctivitis sicca, is the condition of having dry eyes. Symptoms include dryness in the eye, irritation, redness, discharge, blurred vision, and easily fatigued eyes. Symptoms range from mild and occas ...
; 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, PGF, 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 arachidonate-derived analogs by replacing their production with weaker analogs. Eicosapentaenoic acid-derived counterparts of the eoxins have not been described.


Epoxyeicosanoids

The epoxy eicosatrienoic acids (or EETs)—and, presumably, the epoxy eicosatetraenoic acids—have vasodilating actions on
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
,
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
, and other blood vessels as well as on the kidney's reabsorption of sodium and water, and act to reduce
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
and
ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
and other injuries to the heart,
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, and other tissues; they may also act to reduce inflammation, promote the growth and
metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
of certain
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s, promote the growth of new blood vessels, in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, regulate the release of
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s, and in the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
inhibit or reduce pain perception.


The ω−3 and ω−6 series

Arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
(AA; 20:4 ω−6) 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 Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, immunity, and the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
. 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 illness A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...
es. The U.S.
National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
and the
National Library of Medicine The United States National Library of Medicine (NLM), operated by the United States federal government, is the world's largest medical library. Located in Bethesda, Maryland, the NLM is an institute within the National Institutes of Health. I ...
state that there is 'A' level evidence that increased dietary ω−3 improves outcomes in
hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and ...
, secondary
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
prevention, and
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
. There is 'B' level evidence ('good scientific evidence') for increased dietary ω−3 in
primary prevention Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...
of cardiovascular disease,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, and protection from
ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
toxicity in
organ transplant Organ transplantation is a medical procedure in which an organ (anatomy), organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or org ...
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 raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organized in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular me ...
s; (b) change
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
biosynthesis; and (c) directly activate gene transcription. Of these, the action on eicosanoids is the best explored Recent data in 2024 has emerged that neuronal integrity breakdown was reduced by ω−3 treatment in '' APOE*E4'' carriers, suggesting that this treatment may be beneficial for this specific group suggested fish oil supplements might help older adults fight
Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
.


Mechanisms of ω−3 action

In general, the eicosanoids derived from AA promote inflammation, and those from EPA and from
GLA GLA or Gla may refer to: Entertainment * ''GLA'' (album), by Scottish alternative rock band Twin Atlantic * Great Lakes Avengers, a fictional comic hero group Organisations * Gangmasters Licensing Authority, a British regulatory body * Genera ...
(''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
vasoconstrictor Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...
s — TXA2 — are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the
vasodilators Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...
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 Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
''—The
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons.
''
Heat In thermodynamics, heat is energy in transfer between a thermodynamic system and its surroundings by such mechanisms as thermal conduction, electromagnetic radiation, and friction, which are microscopic in nature, involving sub-atomic, ato ...
''—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 Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...
as a component of semen. Between 1929 and 1932,
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and Mildred Burr showed that restricting fat from animals' diets led to a deficiency disease, and first described the
essential fatty acid Essential fatty acids, or EFAs, are fatty acids that are required by humans and other animals for normal physiological function that cannot be synthesized in the body.⁠ As they are not synthesized in the body, the essential fatty acids al ...
s. In 1935, von Euler identified prostaglandin. In 1964, Bergström and
Samuelsson Samuelsson is a Swedish language, Swedish patronymic surname meaning "son of Samuel (name), Samuel". There are alternative spellings such as the English language, English Samuelson and the Norwegian language, Norwegian Samuelsen. It is uncommon a ...
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 The Nobel Prizes ( ; ; ) are awards administered by the Nobel Foundation and granted in accordance with the principle of "for the greatest benefit to humankind". The prizes were first awarded in 1901, marking the fifth anniversary of Alfred N ...
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.


See also

*
Eicosanoid receptor Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that receptor (biochemistry), bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and theref ...
s


References


External links

* {{Authority control