Epoxyeicosatrienoic Acid
   HOME

TheInfoList



OR:

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by 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 ...
by a specific 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 ...
enzymes, termed cytochrome P450
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. They are
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. EETs are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, soluble epoxide hydrolase (sEH), also termed epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range
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; that is, they work locally to regulate the function of the cells that produce them (i.e. they are
autocrine 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) or of nearby cells (i.e. they are
paracrine In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication (biology), cellular communication in which a Cell (biology), cell produces a signal to induce changes in nearby cells, altering the behaviour of ...
agents). The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
s and
brain stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...
s not only by their anti-hypertension action but possibly also by their
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various
cardiovascular diseases 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, rheuma ...
, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of
neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...
. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETs in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.


Structure

EETs are
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 ...
eicosatrienoic acid metabolites 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 ...
(a straight chain
eicosatetraenoic acid Eicosatetraenoic acid (ETA) designates any straight chain tetra-unsaturated 20-carbon fatty acid. These compound are classified as polyunsaturated fatty acids (PUFA). The pure compounds, which are encountered rarely, are colorless oils. Two isomer ...
,
omega-6 fatty acid Omega−6 fatty acids (also referred to as ω−6 fatty acids or ''n''−6 fatty acids) are a family of polyunsaturated fatty acids (PUFA) that share a final carbon-carbon double bond in the ''n''−6 position, that is, the sixth bond, counti ...
). Arachidonic acid has 4 ''cis''
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, which are abbreviated with the notation ''Z'' in the IUPAC
chemical nomenclature Chemical nomenclature is a set of rules to generate systematic name#In chemistry, systematic names for chemical compounds. The nomenclature used most frequently worldwide is the one created and developed by the International Union of Pure and Appli ...
used here. These double bonds are located between carbons 5–6, 8–9, 11–12, and 14–15; arachidonic acid is therefore 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid. Cytochrome P450 epoxygenases attack these double bonds to form their respective eicosatrienoic acid epoxide
regioisomer In chemistry, a structural isomer (or constitutional isomer in the IUPAC nomenclature) of a compound is a compound that contains the same number and type of atoms, but with a different connectivity (i.e. arrangement of bonds) between them. The ...
s viz. 5,6-EET (i.e. 5,6-epoxy-8''Z'',11''Z'',14''Z''-eicosatrienoic acid), 8,9-EET (i.e. 8,9-epoxy-5''Z'',11''Z'',14''Z''-eicosatrienoic acid), 11,12-EET (i.e. 11,12-epoxy-5''Z'',8''Z'',14''Z''-eicosatrienoic acid), or, as drawn in the attached figure, 14,15-EET (i.e. 14,15-epoxy-5''Z'',8''Z'',11''Z''-eicosatrienoic acid). The enzymes generally form both ''R''/''S''
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
s at each former double bond position; for example, cytochrome P450 epoxidases metabolize arachidonic acid to a mixture of 14''R'',15''S''-EET and 14''S'',15''R''-EET.


Production

The
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 ...
(CYP) superfamily of enzymes is distributed broadly throughout bacteria,
archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...
, fungi, plants, animals, and even viruses. The superfamily comprises more than 11,000 genes categorized into 1,000 families. Humans have 57 putatively active CYP genes and 58 CYP
pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...
s; only a relatively few of the active CYP genes code for EET-forming epoxygenases, i.e. protein enzymes with the capacity to attach
atomic 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 ...
to the carbon-carbon double bonds of unsaturated long chain fatty acids such as arachidonic acid. The CYP epoxygenases fall into several subfamilies including CYP1A, CYP2B, CYP2C, CYP2E, CYP2J, and within the CYP3A sub family,
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
; in humans,
CYP2C8 Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsat ...
,
CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...
,
CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...
,
CYP2J2 Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the ''CYP2J2'' gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of ...
, and possibly
CYP2S1 Cytochrome P450 2S1 is a protein that in humans is encoded by the ''CYP2S1'' gene. The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1. Expression CYP2S1 is h ...
isoforms 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 ...
are the main producers of EETs although
CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...
,
CYP2C18 Cytochrome P450 2C18 is a protein that in humans is encoded by the ''CYP2C18'' gene. Function This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactio ...
,
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
,
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 ...
,
CYP4F8 Cytochrome P450 4F8 is a protein that in humans is encoded by the ''CYP4F8'' gene. Function This gene, CYP4F8, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many r ...
, and
CYP4F12 Cytochrome P450 4F12 is a protein that, in humans, is encoded by the ''CYP4F12'' gene. Gene family The ''CYP4F12'' gene encodes a member of the cytochrome P450 superfamily of enzymes. It is located within a cluster of P450 genes on chromosome ...
are capable of producing the EETs and may do so in certain tissues. The CYP epoxygenases can epoxidize any of the double bounds in arachidonic acid but most of them are relatively selective in that they make appreciable amounts of only one or two EETs with 11,12-EET and 14,15-EET accounting for 67–80% of the product made by the cited CYP epoxidases as well as the main EETs made by mammalian tissues. CYP2C9, CYP2J9, and possibly the more recently characterized CYP2S1 appear to be the main produces of the EETs in humans with CYP2C9 being the main EET producer in vascular endothelial cells and CYP2J9 being highly expressed (although less catalytically active than CYP2C) in heart muscle, kidneys, pancreas, lung, and brain. CYP2S1 is expressed in
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, liver, lung, intestine, and spleen and is abundant in human and mouse
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 ...
(i.e.
atheroma An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the tunica intima, inner layer of an arterial wall. The material consists of mostly macrophage, macrophage cells, or debris, containing lipids, calcium and a variabl ...
) plaques as well as inflamed tonsils. ETEs are commonly produced by the stimulation of specific cell types. The stimulation causes arachidonic acid to be released from the ''sn-2'' position of cellular
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 through the action of phospholipase A2-type enzymes and subsequent attack of the released arachidonic acid by a CYP epoxidase. In a typical example of this mechanism,
bradykinin Bradykinin (BK) (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpo ...
or
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
acting through their respective bradykinin receptor B2 and muscarinic acetylcholine receptor M1 or muscarinic acetylcholine receptor M3 stimulate vascular endothelial cells to make and release EETs. The CYP epoxygenases, similar to essentially all CYP450 enzymes, are involved in the metabolism of diverse
xenobiotics A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
and natural compounds. Since many of these same compounds also induce increases in the levels of the epoxygenases, CYP oxygenase levels and consequently EET levels in humans vary widely and are highly dependent on their recent consumption history.


Metabolism of EETs

In cells, the EETs are rapidly metabolized by a cytosolic
soluble epoxide hydrolase Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the ''EPHX2'' gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and con ...
(sEH) which adds water (H2O) across the epoxide to form their corresponding vicinal-
diol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol may also be called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. They are used as protecting gro ...
dihydroxyeicosatrienoic acids (diHETrEs or DHETs), i.e. sEH converts 14,15-ETE to 14,15-dihydroxy-eicosatrienoic acid (14,15-diHETrE), 11,12-ETE to 11,12-diHETrE, 8,9-ETE to 8,9-diHETrE, and 5,6-ETE to 5,6-diHETrE. The product diHETrEs, like their epoxy precursors, are
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
mixtures; for instance, sEH converts 14,15-ETE to a mixture of 14(''S''),15(''R'')-diHETrE and 14(''R''),15(''S'')-diHETrE. However, 5,6-EET is a relatively poor substrate for sEH and in cells is more rapidly metabolized by
cyclooxygenase-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 ...
to form 5,6-epoxy-prostaglandin F1α. Since the diHETrE products are as a rule generally far less active than their epoxide precursors, the sEH pathway of EET metabolism is regarded as a critical EET-inactivating pathway. In some instances, however, the diHETrEs have been found to possess appreciable activity as indicated in the Biological activities section below. Membrane-bound
microsomal epoxide hydrolase In enzymology, a microsomal epoxide hydrolase (mEH) () is an enzyme that catalysis, catalyzes the hydrolysis reaction between an epoxide and water to form a diol. This enzyme plays a role in the uptake of bile salts within the large intestine. ...
(mEH or epoxide hydrolase 1
C 3.2.2.9. C, or c, is the third letter of the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''cee'' (pronounced ), plural ''cees''. History "C ...
can metabolize EETs to their dihydroxy products but is regarded as not contributing significantly to EET inactivation in vivo except perhaps in brain tissue where mEH activity levels far outstrip those of sEH. Furthermore, two other human sEH,
epoxide hydrolase Epoxide hydrolases (EHs), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...
s 3 and 4, have been defined but their role in attacking EETs (and other epoxides) in vivo has not yet been determined. Besides these four epoxide hydrolase pathways, EETs may be acylated into phospholipids in an
acylation In chemistry, acylation is a broad class of chemical reactions in which an acyl group () is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the foll ...
-like reaction. This pathway may serve to limit the action of EETs or store them for future release. EETs are also inactivated by being further metabolized through three other pathways:
beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enter ...
,
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 ...
, and elongation by enzymes involved in
fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes. Two ''De novo synthesis, de novo'' fatty acid syntheses can be distinguished: cytosolic fatty acid synthesis (FAS/FASI) ...
. These alternate to sEH pathways of EET metabolism ensure that blockade of sEH with drugs can increase EET levels only moderately in vivo.


Biological effects

Generally, EETs cause: *
Calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
release from intracellular stores * Increased sodium-hydrogen antiporter activity * Increased cell proliferation * Decreased
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 ...
activity Other effects are specific to certain cells or locations; EETs: * Are cardioprotective after ischemic heart attack and reperfusion. * Act in the corpus cavernosum to maintain penile erection. * Specific epoxidation of EET sites produces endogenous
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 ...
agonists. * Decrease release of
somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...
,
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
and
glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
from endocrine cells. * Stimulate blood vessel formation (
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
). * Cause
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 ...
in the systemic arterial circulation. * Cause
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 ...
of the
liver sinusoid A liver sinusoid is a type of capillary known as a sinusoidal capillary, discontinuous capillary or sinusoid, that is similar to a Capillary#Fenestrated, fenestrated capillary, having discontinuous endothelium that serves as a location for mixing ...
al and pulmonary venous systems. * Increased risk of
tumor adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...
on
endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...
. * Decrease
platelet aggregation Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cytop ...
responses. * Increase
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
growth in neurons. Diol metabolites of the EETs, i.e. the diHETrEs (also termed DHETs), have relatively little or no activity compared to the EETs in most systems. However: * The
chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...
response of human monocytes to
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
chemotactic protein 1) in vivo and in vitro appears to depend on the generation of EETs and conversion of these EETs to diHETrEs. * Certain diHETrEs dilate human coronary arteries with efficacies approaching those of the EETs. * 11,12-diHETrE but not 11,12-EET appears to support the maturation of the myelocyte cell line (i.e. support
myelopoiesis In hematology, myelopoiesis in the broadest sense of the term is the production of bone marrow and of all cells that arise from it, namely, all blood cells. In a narrower sense, myelopoiesis also refers specifically to the regulated formation of ...
) in mice and to promote certain types of
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
in mice and
zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
. * In opposition of the anti-inflammatory actions of EETs, diHETrEs may have some pro-inflammatory actions.


Clinical significance


Regulation of blood pressure

With respect to the regulation of blood pressure as well as the kidneys' regulation of salt and water absorption (which contributes to blood pressure regulation), EETS are counterpoises to another CYP-derived arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE). In humans, the major CYPs making 20-HETE are
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 ...
,
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 ...
. In animal models, 20-HETE raises blood pressure by contracting arteries and stimulating the kidney to reabsorb salt and water to increase the intravascular volume (see 20-Hydroxyeicosatetraenoic acid). EETs have the opposite effects. They are one type of
endothelium-derived hyperpolarizing factor In blood vessels Endothelium-Derived Hyperpolarizing Factor or EDHF is proposed to be a substance and/or electrical signal that is generated or synthesized in and released from the endothelium; its action is to hyperpolarize vascular smooth muscle ...
, i.e. a substance and/or electrical signal synthesized or generated in and released from the vascular endothelium that hyperpolarize nearby vascular smooth muscle cells. This causes these cells to relax and thereby lowers blood pressure. In animal (primarily rodent) models, EETs dilate smaller sized resistance arteries involved in causing hypertension as well as cardiac and renal arteries. They cause smooth muscle hyperpolarization by opening vascular smooth muscle large-conductance calcium-activated potassium channels, opening certain vascular smooth muscle
transient receptor potential channels Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TRP ...
, or facilitating the movement of excitatory signals through
gap junctions Gap junctions are Membrane channel, membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites. Gap junctions were first described as ''close appositions' ...
between endothelium and smooth muscles or between smooth muscles. The actual mechanism(s) involved in these EET-induced effects have not been fully elucidated although some studies implicate EET binding to an unidentified
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 ...
and/or
Gs protein GS may stand for: Businesses and organizations * Goldman Sachs, one of the world's largest global investment banks * Global Star Software, a former Canadian video game publisher * GS (Swedish union), a trade union in Sweden * GS Group, a Korea ...
-linked
G protein–coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
to initiate the signal pathway(s) leading to the cited channel and gap junction changes. With respect to the kidney, studies in rodents find that 20-HETE increases sodium and water reabsorption while the EETs, which are made in the proximal tubules and cortical collecting ducts, reduce sodium ion and water transport at both sites by inhibiting kidney
sodium–hydrogen antiporter The sodium–hydrogen antiporter or sodium–proton exchanger (Na+/H+ exchanger or NHX) is a membrane protein that transports Na+ into the cell, and H+ out of the cell (antiport). Function They are found in the membranes of many cells, and espe ...
(i.e. Na+/H+ exchanger) and/or
epithelial sodium channel The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...
s. Mice lacking either of the EET-producing Cyp2c44 or Cyp4ac44 genes (by
gene knockout Gene knockouts (also known as gene deletion or gene inactivation) are a widely used genetic engineering technique that involves the gene targeting, targeted removal or inactivation of a specific gene within an organism's genome. This can be done t ...
) develop hypertension when fed high sodium or high potassium diets. These and large number of other studies included in the cited references implicate the EETs in the control of at least certain forms of hypertension in rodents. In humans, vascular endothelium production of EETs involves mainly CYP2C9 and numerous indirect studies have implicated CYP epoxygenase, possibly CYP2C9, in producing a product which causes vasodilation. These studies find that selective (but not entirely specific) CYP epoxygenase-inhibiting drugs reduce human vasodilation responses elicited by the vasodilators
bradykinin Bradykinin (BK) (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpo ...
,
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
, and
methacholine Methacholine ( INN, USAN) (trade name Provocholine), also known as acetyl-β-methylcholine, is a synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system. Medical uses Methacholine ...
; this suggests that these vasodilators operate by stimulation the production of EETs. Human studies also find that Caucasian but not African American subjects who have the Lys55Arg
single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
variant in the polyunsaturated fatty epoxide-inactivating enzyme, sEH, express hyperactive sEH and show reduced vasodilation responses to bradykinin. Other studies find that women with pregnancy-induced hypertension and subjects with
renovascular hypertension Renovascular hypertension is a condition in which high blood pressure is caused by the kidneys' hormonal response to narrowing of the renal arteries, arteries supplying the kidneys. When functioning properly this hormonal axis regulates blood pres ...
exhibit low plasma ETE levels. Finally, 11,12-EET has been shown to relax the internal mammary artery in women, indicating that at least this EET has direct vasodilating actions in humans. On the other hand, several studies in humans with
single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
in CYP epxoygenase genes have given negative or confusing results. The most common variant of CYP2J2, rs890293, similarly contradictive or negative results are reported in studies on the rs11572082 (Arg1391Lys) variant of CYP2C8 and the rs1799853 (Arg144Cys) and rs1057910 (Ile359Leu) variants of CYP2C9, all of which code for an epoxygenase with reduced arachidonic acid-metabolizing and EET-forming activities. While many of the cited studies suggest that one or more of the EETs released by vascular endothelial cells are responsible for the actions of the vasodilators and that deficiencies in EET production or excessive EET inactivation by sEH underlie certain types of hypertension in humans, they are not conclusive. They do not exclude a possibility that other polyunsaturated fatty acid epoxides such as those derived from eicosatetraenoic, docosatetraenoic, or linoleic acids made by CYP2C9 or other CYP
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 contribute in small or large part to vasodilation responses and by this action promote blood flow to tissues and function in lowering high blood pressures. Furthermore, the genetic studies conducted to date on SNP variants do not give strong support for an antihypertensive role for the EETs or EET-forming epoxygenases in humans. Recently developed drugs which are metabolically stable analogs of the EETs and thereby mimic the EETs actions or, alternatively of drugs which inhibit sEH and thereby increase EET levels are in the
pre-clinical development In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...
stage for treating human hypertension. Testing for their usefulness in treating human hypertension is made difficult because of: 1) the large number of CYP epoxygenases along with their differing tissue distributions and sensitivities to drug inhibitors; 2) the diversity of EETs made by the CYP epoxygenases, some of which differ in activities; 3) the diversity of fatty acid substrates metabolized by the CYP epoxygenases some of which are converted to epoxides (e.g. the epoxide metabolites of linoleic, docosahexaenoic, eicosapentaenoic acids), which have different activities than the EETs or may even be overtly toxic to humans (see Coronaric acid); 4) the sEH-derived dihydroxy metabolites of the EETs some of which have potent vasodilating effects in the certain vascular networks in rodents and therefore potentially in humans; and 5) the non-specificity and side effects of the latter drugs. As indicated on the ClinicalTrials.gov web site, a
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 ...
-sponsored clinical trial entitled "Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance" has not been completed or reported on although started in 2009.


Heart disease

As indicated elsewhere on this page, EETs inhibit inflammation, inhibit
blood clot A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
formation, inhibit
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
activation, dilate blood vessels including the
coronary arteries The coronary arteries are the arteries, arterial blood vessels of coronary circulation, which transport oxygenated blood to the Cardiac muscle, heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any ...
, reduce certain types of
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 ...
, stimulate the survival of vascular endothelial and cardiac muscle cells by inhibiting
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, promote blood vessel growth (i.e.
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
), and stimulate smooth muscle cell migration; these activities may protect the heart. Indeed, studies on in vivo animal and in vitro animal and human cell model systems indicate that the ETEs reduce
infarct Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the ...
(i.e. injured tissue) size, reduce cardiac arrhythmias, and improve the strength of left ventricle contraction immediately after blockade of coronary artery blood flow in animal models of ischemia-
reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
; EETs also reduce the size of heart enlargement that occurs long after these experiment-induced injuries. Humans with established
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
have higher levels of plasma EETs and higher ratios of 14,15-EET to 14,15-diHETrE (14,15-diHETrE is the less active or inactive metabolite 14,15-EET). This suggests that the EETs serve a protective role in this setting and that these plasma changes were a result of a reduction in cardiac sEH activity. Furthermore,
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
patients who had lower levels of EETs/14,15-di-ETE ratios exhibited evidence of a poorer prognosis based on the presence of poor prognostic indicators, cigarette smoking, obesity, old age, and elevation in inflammation markers.


Strokes and seizures

Indirect studies in animal models suggest that EETs have protective effects in
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
s (i.e. cerbrovasular accidents). Thus, sEH inhibitors and sEH-
gene knockout Gene knockouts (also known as gene deletion or gene inactivation) are a widely used genetic engineering technique that involves the gene targeting, targeted removal or inactivation of a specific gene within an organism's genome. This can be done t ...
have been shown to reduce the damage to brain that occurs in several different models of
ischemic stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...
; this protective effect appears due to a reduction in systemic blood pressure and maintenance of blood flow to ischemic areas of the brain by arteriole dilation as a presumed consequence of inhibiting the degradation of EETs (and/or other fatty acid epoxides). sEH-gene knockout mice were also protected from that brain damage that followed induced-
subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid (brain), arachnoid membrane and the pia mater surrounding the human brain, brain. Symptoms may include a thunderclap headache, severe heada ...
; this protective effect appeared due to a reduction in cerebral edema which was also presumable due to the prolongation of EET half-lives. 14,15-EET levels have been shown to be elevated in the
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
of humans suffering subarachnoid hemorrhage. sEH inhibitors and gene knockout also reduce the number and severity of
epileptic seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
s in several animal models; this effect is presumed due to the actions of EETs (and other epoxide fatty acids) in reducing cerebral blood flow changes, and reducing neuron production of
neuroactive steroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...
s, reducing neuroinflammation,


Portal hypertension

Portal hypertension or hypertension in the venous
hepatic portal system In human anatomy, the hepatic portal system or portal venous system is a system of veins comprising the portal vein and its tributaries. The other portal venous system in the body is the hypophyseal portal system. Structure Large veins that ar ...
of blood flow is defined as an increase in portal pressure above normal values of 10
millimeter of mercury A millimetre of mercury is a manometric unit of pressure, formerly defined as the extra pressure generated by a column of mercury one millimetre high. Currently, it is defined as exactly , or approximately 1 torr =  atmosphere = &nbs ...
. It is a serious, sometimes life-threatening complication of various diseases such as liver
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
,
liver fibrosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
, massive
fatty liver Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper r ...
,
portal vein thrombosis Portal vein thrombosis (PVT) is a vascular disease of the liver that occurs when a blood clot occurs in the hepatic portal vein, which can lead to increased pressure in the portal vein system and reduced blood supply to the liver. The mortality ...
, liver
schistosomiasis Schistosomiasis, also known as snail fever, bilharzia, and Katayama fever is a neglected tropical helminthiasis, disease caused by parasitism, parasitic Schistosoma, flatworms called schistosomes. It affects both humans and animals. It affects ...
, massive liver involvement in
miliary tuberculosis Miliary tuberculosis is a form of tuberculosis that is characterized by a wide dissemination into the human body and by the tiny size of the lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest radiograph of many tiny ...
or
sarcoidosis Sarcoidosis (; also known as Besnier–Boeck–Schaumann disease) is a disease involving abnormal collections of White blood cell, inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph n ...
, and obstruction of the venous circuit at any level between liver and right heart (see
Portal hypertension Portal hypertension is defined as increased portal venous pressure, with a hepatic venous pressure gradient greater than 5 mmHg. Normal portal pressure is 1–4 mmHg; clinically insignificant portal hypertension is present at portal pressures 5 ...
). Vascular contraction in the portal system is mediated by several agents:
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
,
carbon monoxide Carbon monoxide (chemical formula CO) is a poisonous, flammable gas that is colorless, odorless, tasteless, and slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the si ...
,
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 ...
I2, and
endothelium-derived hyperpolarizing factor In blood vessels Endothelium-Derived Hyperpolarizing Factor or EDHF is proposed to be a substance and/or electrical signal that is generated or synthesized in and released from the endothelium; its action is to hyperpolarize vascular smooth muscle ...
s (EDHFs). EDHFs include
endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...
,
angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...
,
thromboxane A2 Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by a ...
, certain
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, and the EETs. In portal hypertension, portal vein endothelium appears to be dysfunctional in that it overproduces EDHFs. The EETs, particularly 11,12-EET, have a quite different effect on the
liver sinusoid A liver sinusoid is a type of capillary known as a sinusoidal capillary, discontinuous capillary or sinusoid, that is similar to a Capillary#Fenestrated, fenestrated capillary, having discontinuous endothelium that serves as a location for mixing ...
al veins than on arteries of the
systemic circulation In vertebrates, the circulatory system is a organ system, system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of ...
: they constrict the sinusoids. Levels of EETs in the plasma and liver of patients with cirrhosis and portal hypertension are reportedly elevated compared to normal subjects. These and other findings have led to the proposal that portal endothelium-derived EETs, perhaps acting in cooperation with another EDHF, endothelin, contribute to portal hypertension.


Cancer

The forced over-expression of CYP2J2 in or the addition of an EET to cultured human Tca-8113 oral squamous cancer cells, lung cancer
A549 cell A549 cells are adenocarcinoma, adenocarcinomic human Pulmonary alveolus, alveolar basal lamina, basal epithelial cell (biology), cells, and constitute a cell line that was first developed in 1972 by D. J. Giard, et al. through the removal and cel ...
s and NCL-H446 cells, HepG2 liver cancer cells, LS-174 colon cancer cells,
SiHa Siha is one of the seven administrative districts of Kilimanjaro Region in Tanzania. The district covers approximately . It is bordered to the west by Meru District in Arusha Region and to the northeast by Rombo District and the southeast Hai Dis ...
uterine cervix cancer cells,
U251 The NCI-60 cancer cell line panel is a group of 60 human cancer cell lines used by the National Cancer Institute (NCI) for the screening of compounds to detect potential anticancer activity. Purpose The screening procedure is called the NCI-6 ...
glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...
cancer cells, ScaBER urinary bladder cancer cells, and K562 erythroleukemia and HL-60
promyelocyte A promyelocyte (or progranulocyte) is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte. Promyelocytes measure 12–20 microns in diameter. The Cell nucleus, nucleus of a promyelocyte is approximately the ...
leukemic blood cancer cells caused an increase in their survival and proliferation. Putative inhibitors of CYP2J2 inhibit the growth in culture of several human cancer cell lines that express relatively high levels of CYP2J2 viz., Tca-8113 cells,
HeLa HeLa () is an immortalized cell line used in scientific research. It is the oldest human cell line and one of the most commonly used. HeLa cells are durable and prolific, allowing for extensive applications in scientific study. The line is ...
uterine cervix cell lines, A549 cells,
MDA-MB-435 The NCI-60 cancer cell line panel is a group of 60 human cancer cell lines used by the National Cancer Institute (NCI) for the screening of compounds to detect potential anticancer activity. Purpose The screening procedure is called the NCI ...
breast cells, and HepG2 cells but they had no significant inhibitory effects on two cell lines that expressed little or no CYP2J2. A putative inhibitor of CYPJ2 also inhibited the growth of human K562 erythroleukemia in a
mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
model as well as the growth of mouse el4 lymphoma cells in mice that were forced to overexpress CYP2J2 cells in their vascular epithelium. Forced expression of CYP2J2 also enhanced, while forced inhibition of its expression (using
Small interfering RNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA, double-stranded non-coding RNA, non-coding RNA, RNA molecules, typically 20–24 base pairs in length, similar to microR ...
) reduced, the survival, growth, and metastasis of
MDA-MB-231 Scientists study the behaviour of isolated cells grown in the laboratory for insights into how cells function in the body in health and disease. Experiments using cell culture are used for developing new diagnostic tests and new treatments for dise ...
human breast carcinoma cells in the mouse model and likewise enhanced or reduced, respectively, the survival and growth of these cells in culture. Further studies found that the expression of CYP2J2 was in increased in the malignant cells, relative to the nearby normal cells, in the following specimens taken from humans suffering
squamous-cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
and
adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
types of
esophageal cancer Esophageal cancer (American English) or oesophageal cancer (British English) is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include dysphagia, difficulty in swallowing and weigh ...
and
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
,
small cell lung carcinoma Small-cell carcinoma, also known as oat cell carcinoma, is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tr ...
,
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
,
stomach cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a numb ...
,
liver cancer Liver cancer, also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy, is cancer that starts in the liver. Liver cancer can be primary in which the cancer starts in the liver, or it can be liver metastasis, or secondar ...
, and
colon adenocarcinoma Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...
; this CYP was also highly expressed in the malignant cells of patients with acute leukemia, chronic leukemia, and lymphoma. As a group, patients with these cancers exhibited increased levels of EETs in their urine and blood samples. Studies of the CYP epoxygenases have not been restricted to the CYP2J subfamily. Reduction in the expression of CYP3A4 or CYP2C using small interfering RNA inhibits the growth of cultured
MCF7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers ...
, T47D, and MDA-MB-231 human breast cancer cells; in these studies 14,15-EET stimulated the proliferation of cultured
MCF7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers ...
cells, reduction in the expression of CYP3A4 by small interference RNA methods, inhibited these cells from proliferating, and 14,15-ETE reversed the effect of CYP3A4 interference; in other studies, the forced overexpression of CYP3A4 stimulated the growth of human liver cancer (
hepatoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...
) cell line, Hep3 . In human breast cancer, not only CYP2J2 but also CYP2C8 and CYP2C9 levels appear elevated while sEH levels appear reduced in malignant compared to nearby normal tissues; associated with this finding, the levels of 14,15-EET as well as the levels of 14,15-EET plus 14,15-dihydroxy-EET were significantly elevated in the cancerous compared to noncancerous cells and the levels of CYP2C8 and CYP2C9 proteins correlated positively and sEH levels correlated negatively with the tumor cells rate of proliferation as accessed by their Ki67 levels while CYP2J2 levels correlated positively with poorer prognosis as predicted tumor histological grade and tumor size. The cited findings suggest that various CYP epoxygenases along with the epoxide metabolites which they make promote the growth and spread of diverse types of cancer in animals and humans. Their effects may reflect the ability of the epoxide metabolites to stimulate the proliferation and survival of the target cancer cells but perhaps also to stimulate these cells to trigger new capillary formation (see ), invade new tissues, and
metastasize 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, ...
. A series of drugs derived from
Terfenadine Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triluda ...
have been shown to inhibit CYP2J2 and to suppress the proliferation and cause the
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
of various types of human cancer cell lines in culture as well as in animal models. However, clinical studies targeting CYP epoxygenases and EETs and to successfully suppress cancer in humans have not been reported. Pro-angiogenic and tumor promoting effects of EETs have been attributed to downstream
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 ...
(COX)-derived metabolites. Dual sEH/COX inhibitors or sEH inhibitors supplemented with an enhanced
omega-3 fatty acid Omega−3 fatty acids, also called omega−3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond three atoms away from the terminal methyl group in their ...
diet and a depleted
omega-6 fatty acid Omega−6 fatty acids (also referred to as ω−6 fatty acids or ''n''−6 fatty acids) are a family of polyunsaturated fatty acids (PUFA) that share a final carbon-carbon double bond in the ''n''−6 position, that is, the sixth bond, counti ...
diet have been shown to induce significant anti-angiogenic effects and blunt tumor growth.


Inflammation

In vitro and animal model studies indicate that the EETs possess
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
activity that is directed toward reducing, resolving, and limiting the damage caused by inflammation. Most of these studies have focused on circulating
leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
, blood vessel endothelium, and the occlusion of blood vessels due to pathological blood clotting. EETs a) inhibit vascular endothelial cells from expressing
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s such as
VCAM-1 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the ''VCAM1'' gene. VCAM-1 functions as a cell adhesion molecule. Str ...
,
ICAM-1 ICAM-1 (Intercellular adhesion molecule, Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is ty ...
, and
E-selectin E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endotheli ...
thereby limiting circulating
leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
from adhering to blood vessel endothelium and migrating across this endothelium into tissues; 2) inhibit the expression and activity of
cyclooxygenase-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 ...
in blood
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
thereby reducing their production of pro-inflammatory metabolites of arachidonic acid such as
prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnanc ...
; 3) inhibit platelet aggregation thereby reducing
thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
(i.e. blood clot) formation; 4) promote
fibrinolysis Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other c ...
thereby dissolving blood clots; and 5) inhibit vascular smooth muscle cell proliferation thereby reducing blood vessel
hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
and narrowing.


Diabetes, non-alcoholic fatty liver disease, and kidney disease

EETs, pharmacological inhibition of sEH, and/or inhibition of sEH expression enhance insulin actions on animal tissues in vitro and have protective effects in ameliorating insulin resistance as well as many of the neurological and kidney complications of diabetes in various animal models of diabetes; the studies suggest that the EETs have beneficial effects in
type I diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone required ...
as well as
type II diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
. Treatment of EET analog is beneficial for hepatic insulin signaling in mouse model of insulin resistance. These interventions also gave beneficial results in animal models of
non-alcoholic fatty liver disease An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...
and certain types inflammation-related kidney diseases including chronic kidney disease, renal ischemia-reperfusion injury, and
polycystic kidney disease Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These ...
. The protective role of EETs in these animal model diseases may reflect, at least in part, their anti-inflammatory actions.


Pain

EETs have been shown to have anti-hyperalgesic and pain-relieving activity in several animal models of pain including
nociception In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...
resulting from tissue injury,
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
peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
(see
Neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...
) including pain secondary to experimentally induced
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
in mice. The epoxides of omega-3 fatty acids appear far stronger and more involved in the relief of pain than the EETs (see
Epoxydocosapentaenoic acid Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases meta ...
).


References

{{Transient receptor potential channel modulators Eicosanoids Epoxides Cell biology Immunology Inflammations Blood pressure Human physiology Animal physiology