12-Hydroxyheptadecatrienoic acid

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12-Hydroxyheptadecatrienoic acid
12-Hydroxyheptadecatrienoic acid.svg
Names
Preferred IUPAC name
(5Z,8E,10E,12S)-12-Hydroxyheptadeca-5,8,10-trienoic acid
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.161.462 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
  • InChI=1S/C17H28O3/c1-2-3-10-13-16(18)14-11-8-6-4-5-7-9-12-15-17(19)20/h5-8,11,14,16,18H,2-4,9-10,12-13,15H2,1H3,(H,19,20)/b7-5-,8-6+,14-11+/t16-/m0/s1
    Key: KUKJHGXXZWHSBG-WBGSEQOASA-N
  • InChI=1/C17H28O3/c1-2-3-10-13-16(18)14-11-8-6-4-5-7-9-12-15-17(19)20/h5-8,11,14,16,18H,2-4,9-10,12-13,15H2,1H3,(H,19,20)/b7-5-,8-6+,14-11+/t16-/m0/s1
    Key: KUKJHGXXZWHSBG-WBGSEQOABE
  • CCCCC[C@@H](/C=C/C=C/C/C=C\CCCC(=O)O)O
Properties
C17H28O3
Molar mass 280.408 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. [1] [2] 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

Contents

Production

Primary source

Cyclooxygenase-1 and cyclooxygenase-2 metabolize arachidonic acid to the 15-hydroperoxy, 20 carbon prostaglandin (PG) intermediate, PGG2, and then to the 15-hydroxy, 20 carbon intermediate, prostaglandin H2 (PGH2). Thromboxane synthase further metabolizes PGH2 to the 20 carbon product, Thromboxane A2, the 17 carbon product, 12-HHT, and the 3 carbon product malonyldialdehyde. Platelets express cyclooxygenase and thromboxane synthase enzymes, producing PGG2, PGH2, and TXA2 in response to platelet aggregating agents such as thrombin; these metabolites act as autocrines by feeding back to promote further aggregation of their cells of origin and as paracrines by recruiting nearby platelets into the response as well as exerting effects on other nearby tissues such as contracting blood vessels. [3] These effects combine to trigger blood clotting and limiting blood loss. 12-HHT is a particularly abundant product of these pro-clotting responses, accounting for about one third of the total amount of arachidonic acid metabolites formed by physiologically stimulated human platelets. [4] Its abundant production during blood clotting, the presence of cyclooxygenases and to a lesser extent thromboxane synthase in a wide range of cell types and tissue, and its production by other pathways imply that 12-HHT has one or more important bioactivities relevant to clotting and, perhaps, other responses.

Other sources

Various cytochrome P450 enzymes (e.g. CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2S1, and CYP3A4) metabolize PGG2 and PGH2 to 12-HHT and MDA. [5] [6] [7] While the latter studies were conducted using recombinant cytochrome enzymes or sub-fractions of disrupted cells, the human monocyte, a form of blood circulating leukocyte, increases its expression of CYP2S1 when forced to differentiate into a macrophage phenotype by interferon gamma or lipopolysaccharide (i.e. endotoxin); associated with these changes, the differentiated macrophage metabolized arachidonic acid to 12-HHT by a CYP2S1-dependent mechanism. [8] Future studies, therefore may show that cytochromes are responsible for 12-HHT and MDA production in vivo.

PGH2, particularly in the presence of ferrous iron (FeII), ferric iron (FeIII), or hemin, rearranges non-enzymatically to a mixture of 12-HHT and 12-HHT's 8-cis isomer, i.e., 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid. [1] [6] [2] [9] This non-enzymatic pathway may explain findings that cells can make 12-HHT in excess of TXA2 and also in the absence of active cycloxygenase and/or thromboxane synthase enzymes. [10]

Further metabolism

12-HHT is further metabolized by 15-hydroxyprostaglandin dehydrogenase (NAD+) in a wide variety of human and other vertebrate cells to its 12-oxo (also termed 12-keto) derivative, 12-oxo-5Z,8E,10E-heptadecatrienoic acid (12-oxo-HHT or 12-keto-HHT). [11] [12] [13] [14] Pig kidney tissue also converted 12-HHT to 12-keto-5Z,8E-heptadecadienoic acid (12-oxo-5Z,8E-heptadecadienoic acid) and 12-hydroxy-heptadecadienoic acid. [11]

Acidic conditions (pH~1.1-1.5) cause 12-HHT to rearrange in a time- and temperature-dependent process to its 5-cis isomer, 12-hydroxy-5E,8E,10E-heptadecatrienoic acid. [15]

Activities and clinical significance

Early studies

Fourteen years after the first publication on its detection in 1973, 12-HHT was reported to stimulate fetal bovine aortic and human umbilical vein endothelial cells to metabolize arachidonic acid to Prostacyclin I2 (PGI2), a powerful inhibitor of platelet activation and stimulator of Vasodilation (see Prostacyclin synthase); it did not, however, alter arachidonic acid metabolism in human platelets. [4] Shortly thereafter, 12-HHT was reported to inhibit the chemotaxis-blocking effect of a human monocyte-derived factor on human moncytes [16] while the immediate metabolite of 12-HHT, 12-oxo-HT, was reported to stimulate the chemotasis of human neutrophils. [11] and to inhibit platelet aggregation responses to various agents by stimulating platelets to raise their levels of Cyclic adenosine monophosphate (cAMP), an intracellular signal that serves broadly to inhibit platelet activation. [11] These studies were largely overlooked; in 1998 and 2007 publications, for example, 12-HHT was regarded as either inactive or without significant biological activity. [17] [9] Nonetheless, this early work suggested that 12-HHT may serve as a contributor to monocyte- and neutrophil-based inflammatory responses and 12-oxo-HT may serve as a counterpoise to platelet aggregation responses elicited or promoted by TXA2. Relevant to the latter activity, a later study showed that this inhibitory effect was due to the ability of 12-oxo-HT to act as a partial antagonist of the Thromboxane receptor: it blocks TXA2 binding to its receptor and thereby the responses of platelets and possibly other tissues to TXA2 as well as agents that depend on stimulating TXA2 production for their activity. [18] Thus, 12-HHT forms simultaneously with, and by stimulating PGI2 production, inhibits TXA2-mediated platelet activation responses while 12-oxo-HT blocks TXA2 receptor binding to reduce not only TXA2-induced thrombosis and blood clotting but possibly also vasospasm and other actions of TXA2. In this view, thromboxane synthase leads to the production of a broadly active arachidonic acid metabolite, TXA2, plus two other arachidonic acid metabolites, 12-HHT and 12-oxo-HT, that serve indirectly to stimulate PGI2 production or directly as a receptor antagonist to moderate TXA2's action, respectively. This strategy may be essential for limiting the deleterious thrombotic and vasospastic activities of TXA2.

12-HHT is a BLT2 receptor agonist

Leukotriene B4 (i.e. LTB4) is an arachidonic acid metabolite made by the 5-lipoxygenase enzyme pathway. It activates cells through both its high affinity (Dissociation constant [Kd] of 0.5-1.5 nM) Leukotriene B4 receptor 1 (BLT1 receptor) and its low affinity BLT2 receptor (Kd=23 nM); both receptors are G protein coupled receptors that, when ligand-bound, activate cells by releasing the Gq alpha subunit and pertussis toxin-sensitive Gi alpha subunit from Heterotrimeric G proteins. [19] [20] BLT1 receptor has a high degree of ligand-binding specificity: among a series of hydroxylated eicosanoid metabolites of arachidonic acid, it binds only LTB4, 20-hydroxy-LTB4, and 12-epi-LTB4; among this same series, BLT2 receptor has far less specificity in that it binds not only LTB4, 20-hydroxy-LTB4, and 12-epi-LTB4 but also 12(R)-HETE and 12(S)-HETE (i.e. the two stereoisomers of 12-Hydroxyeicosatetraenoic acid) and 15(S)-HpETE and 15(S)-HETE (i.e. the two stereoisomers of 15-Hydroxyicosatetraenoic acid). [21] The BLT2 receptor's relative affinities for finding LTB4, 12(S)-HETE, 12(S)-HpETE, 12(R)-HETE, 15(S)-HETE, and 20-hydroxy-LTB4 are ~100, 10, 10, 3, 3, and 1, respectively. All of these binding affinities are considered to be low and therefore indicating that some unknown ligand(s) might bind BLT2 with high affinity. In 2009, 12-HHT was found to bind to the BLT2 receptor with ~10-fold higher affinity than LTB4; 12-HHT did not bind to the BLT1 receptor. [17] Thus, the BLT1 receptor exhibits exquisite specificity, binding 5(S),12(R)-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoic acid (i.e. LTB4) but not LTB4's 12(S) or 6Z isomers while the BLT2 receptor exhibits a promiscuous finding pattern. [22] Formyl peptide receptor 2 is a relevant and well-studied example of promiscuous receptors. Initially thought to be a second and low affinity receptor for the neutrophil tripeptide chemotactic factor, N-formyl-met-leu-phe, subsequent studies showed that it was a high affinity receptor for the arachidonic acid metabolite, lipoxin A4, but also bound and was activated by a wide range of peptides, proteins, and other agents. [23] BLT2 may ultimately prove to have binding specificity for a similarly broad range of agents.

The production of LTB4 and expression of BLT1 by human tissues are largely limited to bone marrow-derived cells such as the neutrophil, eosinophil, mast cell, and various types of lymphocytes [20] [22] and accordingly are regarded primarily as contributing to the many human defensive and pathological (ulcerative colitis, arthritis, asthma, etc.) inflammatory responses which are mediated by these cell types. Drugs that inhibit LTB4 production or binding to BLT1 are in use or development for the latter diseases. [24] [25] [26] In contrast, the production of 12-HHT and expression of BLT2 receptors by human tissues is far wider and more robust than that of the LTB4/BLT2 receptor axis. [27] [20] [22] Recent studies indicate that the role(s) of the 12-HHT/BLT2 receptor axis in human physiology and pathology may be very different from those of the LTB4/BLT1 axis.

Recent studies on 12-HHT/BLT2 receptor activities

Inflammation and allergy

12-HHT stimulates chemotactic responses in mouse bone marrow mast cells, which naturally express BLT2 receptors, as well as in Chinese hamster ovary cells made to express these receptors by transfection. [17] These findings suggest that the 12-HHT/BLT2 receptor pathway may support the pro-inflammatory (i.e. chemotactic) actions of the LTB4/BLT1 pathway.

On the other hand, the immortalized human skin cell line HaCaT expresses BLT2 receptors and responds to ultraviolet B (UVB) radiation by generating toxic reactive oxygen species which in turn cause the HaCaT cells to die by activating apoptotic pathways in a BLT2 receptor-dependent reaction. Topical treatment of mouse skin with a BLT2 receptor antagonist, LY255283, protects against UVB radiation-induced apoptosis and BLT2-overexpressing transgenic mice exhibited significantly more extensive skin apoptosis in response to UVB irradiation. [28] Furthermore, 12-HHT inhibits HaCaT cells from synthesizing interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation, in response to UVB radiation. [29] These results suggest that the 12-HHT/BLT2 axis can act to suppress inflammation by promoting the orderly death of damaged cells and blocking IL-6 production. Opposition between the pro-inflammatory LTB4/BLT1 and anti-inflammatory actions of the 12-HHT/BLT2 axes occurs in another setting. In a mice model of ovalbumin-induced allergic airway disease, 12-HHT and its companion cyclooxygenase metabolites, Prostaglandin E2 and Prostaglandin D2, but not 12 other lipoxygenase or cycloxygenase metabolites, showed a statistically significantly increase in bronchoalveolar lavage fluid levels after intratracheal ovalbumin challenge; after this challenge, only 12-HHT, among the monitored BLT2 receptor-activating ligands (LTB4, the 12(S) stereoisomer of 12-HETE, and 15(S)-HETE) attained levels capable of activating BLT2 receptors. Also, BLT2 knockout mice exhibited a greatly enhanced response to ovalbumin challenge. Finally, BLT2 receptor expression was significantly reduced in allergy-regulating CD4+ T cells from patients with asthma compared to healthy control subjects. [30] Unlike LTB4 and its BLT1 receptor, which are implicated in contributing to allergen-based airway disease in mice and humans, [31] 12-HHT and its BLT2 receptor appear to suppress this disease in mice and may do so in humans. [30] [32] While further studies to probe the role of the 12-HHT/BLT2 axis in human inflammatory and allergic diseases, the current studies indicate that 12-HHT, acting through BLT2, may serve to promote or limit, inflammatory and to promote allergic responses.

Wound healing

High dose aspirin treatment (aspirin, at these doses, inhibits cyclooxygenases-1 and -2 to block their production of 12-HHT), thromboxane synthase knockout, and BLT2 receptor knockout but not TXA2 receptor knockout impair keratinocyte-based re-epithelialization and thereby closure of experimentally induced wounds in mice while a synthetic BLT2 receptor agonist accelerates wound closure not only in this mouse model but also in the db/db mouse model of obesity, diabetes, and dyslipidemia due to leptin receptor deficiency. 12-HHT accumulated in the wounds of the former mouse model. Companion studies using an in vitro scratch test assay indicated that 12-HHT stimulated human and mouse keratinocyte migration by a BLT2 receptor-dependent mechanism that involved the production of tumor necrosis factor α and metalloproteinases. [33] These results indicate that the 12-HHT/BLT2 receptor axis is a critical contributor to wound healing in mice and possibly humans. The axis operates by recruiting the movement of keratinocytes to close the wound. This mechanism may underlie the suppression of wound healing that accompanies the high dose intake of aspirin and, based on mouse studies, other non-steroidal anti-inflammatory agents (NSAID) in humans. [34] [22] Synthetic BLT2 agonists may be useful for speeding the healing of chronic ulcerative wounds, particularly in patients with, for example diabetics, that have impaired wound healing. [33] [35] [22]

Cancer

A large number of studies have associated BLT2 and, directly or by assumption, 12-HHT in the survival, growth, and/or spread of various human cancers. BLT2, also called leukotriene B4 receptor 2, is closely associated with 12-HHT in stimulation of metastasis (malignant behavior of tumor cells) in the following cancers:

See also

Related Research Articles

<span class="mw-page-title-main">Arachidonic acid</span> Fatty acid used metabolically in many organisms

Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the Neo-Latin word arachis (peanut), but peanut oil does not contain any arachidonic acid.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

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

<span class="mw-page-title-main">Leukotriene</span> Class of inflammation mediator molecules

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

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-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

<span class="mw-page-title-main">Thromboxane-A synthase</span> Mammalian protein found in Homo sapiens

Thromboxane A synthase 1 , also known as TBXAS1, is a cytochrome P450 enzyme that, in humans, is encoded by the TBXAS1 gene.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

<span class="mw-page-title-main">Thromboxane A2</span> Chemical compound

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 activating the thromboxane receptor, which results in platelet-shape change, inside-out activation of integrins, and degranulation. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. Thromboxane A2 is also a known vasoconstrictor and is especially important during tissue injury and inflammation. It is also regarded as responsible for Prinzmetal's angina.

Prostaglandin H<sub>2</sub> Chemical compound

Prostaglandin H2 is a type of prostaglandin and a precursor for many other biologically significant molecules. It is synthesized from arachidonic acid in a reaction catalyzed by a cyclooxygenase enzyme. The conversion from Arachidonic acid to Prostaglandin H2 is a two step process. First, COX-1 catalyzes the addition of two free oxygens to form the 1,2-Dioxane bridge and a peroxide functional group to form Prostaglandin G2. Second, COX-2 reduces the peroxide functional group to a Secondary alcohol, forming Prostaglandin H2. Other peroxidases like Hydroquinone have been observed to reduce PGG2 to PGH2. PGH2 is unstable at room temperature, with a half life of 90-100 seconds, so it is often converted into a different prostaglandin.

<span class="mw-page-title-main">ALOX15</span> Lipoxygenase found in humans

ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function

<span class="mw-page-title-main">PTGS1</span>

Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene. In humans it is one of two cyclooxygenases.

<span class="mw-page-title-main">GPR31</span> Protein in humans

G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.

Leukotriene B<sub>4</sub> receptor 2 Protein-coding gene in the species Homo sapiens

Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice.

<span class="mw-page-title-main">5-Hydroxyeicosatetraenoic acid</span> Chemical compound

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-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(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).

<span class="mw-page-title-main">12-Hydroxyeicosatetraenoic acid</span> Chemical compound

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 5Z,8Z,10E,14Z Cis–trans isomerism configuration (Z=cis, E=trans) in its four double bonds. It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase (i.e. ALOX12) enzyme(s). However, the term 12-HETE is ambiguous in that it has been used to indicate not only the initially detected "S" stereoisomer, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE or 12S-HETE), made by platelets, but also the later detected "R" stereoisomer, 12(R)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (also termed 12(R)-HETE or 12R-HETE) made by other tissues through their 12R-lipoxygenase enzyme, ALOX12B. The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. Unlike hormones which are secreted by cells, travel in the circulation to alter the behavior of distant cells, and thereby act as Endocrine signalling agents, these arachidonic acid metabolites act locally as Autocrine signalling and/or Paracrine signaling agents to regulate the behavior of their cells of origin or of nearby cells, respectively. In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances.

<span class="mw-page-title-main">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5S,15S-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE, a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

Eoxins are proposed to be a family of proinflammatory eicosanoids. They are produced by human eosinophils, mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues. These cells produce the eoxins by initially metabolizing arachidonic acid, an omega-6 (ω-6) fatty acid, via any enzyme possessing 15-lipoxygenase activity. The product of this initial metabolic step, 15(S)-hydroperoxyeicosatetraenoic acid, is then converted to a series of eoxins by the same enzymes that metabolize the 5-lipoxygenase product of arachidonic acid metabolism, i.e. 5-Hydroperoxy-eicosatetraenoic acid to a series of leukotrienes. That is, the eoxins are 14,15-disubstituted analogs of the 5,6-disubstituted leukotrienes.

<span class="mw-page-title-main">5-Oxo-eicosatetraenoic acid</span> Chemical compound

5-Oxo-eicosatetraenoic acid is a Nonclassic eicosanoid metabolite of arachidonic acid and the most potent naturally occurring member of the 5-HETE family of cell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell and/or exits this cell to stimulate nearby cells. 5-Oxo-ETE can stimulate various cell types particularly human leukocytes but possesses its highest potency and power in stimulating the human eosinophil type of leukocyte. It is therefore suggested to be formed during and to be an important contributor to the formation and progression of eosinophil-based allergic reactions; it is also suggested that 5-oxo-ETE contributes to the development of inflammation, cancer cell growth, and other pathological and physiological events.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

References

  1. 1 2 Wlodawer, P; Samuelsson, B (1973). "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry. 248 (16): 5673–8. doi: 10.1016/S0021-9258(19)43558-8 . PMID   4723909.
  2. 1 2 Hamberg, M; Samuelsson, B (1974). "Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets". Proceedings of the National Academy of Sciences of the United States of America. 71 (9): 3400–4. Bibcode:1974PNAS...71.3400H. doi: 10.1073/pnas.71.9.3400 . PMC   433780 . PMID   4215079.
  3. ↑ Wong, S. L.; Wong, W. T.; Tian, X. Y.; Lau, C. W.; Huang, Y (2010). Prostaglandins in action indispensable roles of cyclooxygenase-1 and -2 in endothelium-dependent contractions. Advances in Pharmacology. Vol. 60. pp. 61–83. doi:10.1016/B978-0-12-385061-4.00003-9. ISBN   9780123850614. PMID   21081215.
  4. 1 2 Sadowitz, P. D.; Setty, B. N.; Stuart, M (1987). "The platelet cyclooxygenase metabolite 12-L-hydroxy-5, 8, 10-hepta-decatrienoic acid (HHT) may modulate primary hemostasis by stimulating prostacyclin production". Prostaglandins. 34 (5): 749–63. doi:10.1016/0090-6980(87)90297-8. PMID   3124219.
  5. ↑ Plastaras, J. P.; Guengerich, F. P.; Nebert, D. W.; Marnett, L. J. (2000). "Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde". The Journal of Biological Chemistry. 275 (16): 11784–90. doi: 10.1074/jbc.275.16.11784 . PMID   10766802.
  6. 1 2 Hecker, M; Ullrich, V (1989). "On the mechanism of prostacyclin and thromboxane A2 biosynthesis". The Journal of Biological Chemistry. 264 (1): 141–50. doi: 10.1016/S0021-9258(17)31235-8 . PMID   2491846.
  7. ↑ Bui, P; Imaizumi, S; Beedanagari, S. R.; Reddy, S. T.; Hankinson, O (2011). "Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids". Drug Metabolism and Disposition. 39 (2): 180–90. doi:10.1124/dmd.110.035121. PMC   3033693 . PMID   21068195.
  8. ↑ Frömel, T; Kohlstedt, K; Popp, R; Yin, X; Awwad, K; Barbosa-Sicard, E; Thomas, A. C.; Lieberz, R; Mayr, M; Fleming, I (2013). "Cytochrome P4502S1: A novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques". Basic Research in Cardiology. 108 (1): 319. doi:10.1007/s00395-012-0319-8. PMID   23224081. S2CID   9158244.
  9. 1 2 John, H; Cammann, K; Schlegel, W (1998). "Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid". Prostaglandins & Other Lipid Mediators. 56 (2–3): 53–76. doi:10.1016/s0090-6980(98)00043-4. PMID   9785378.
  10. ↑ Matsunobu, T; Okuno, T; Yokoyama, C; Yokomizo, T (2013). "Thromboxane a synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand". The Journal of Lipid Research. 54 (11): 2979–87. doi:10.1194/jlr.M037754. PMC   3793602 . PMID   24009185.
  11. 1 2 3 4 Hecker, M; Ullrich, V (1988). "12(S)-Hydroxy-5,8,10 (Z,E,E)-heptadecatrienoic acid (HHT) is preferentially metabolized to its 12-keto derivative by human erythrocytes in vitro". Eicosanoids. 1 (1): 19–25. PMID   3272822.
  12. ↑ Bergholte, J. M.; Soberman, R. J.; Hayes, R; Murphy, R. C.; Okita, R. T. (1987). "Oxidation of 15-hydroxyeicosatetraenoic acid and other hydroxy fatty acids by lung prostaglandin dehydrogenase". Archives of Biochemistry and Biophysics. 257 (2): 444–50. doi:10.1016/0003-9861(87)90589-3. PMID   3662534.
  13. ↑ Agins, A. P.; Thomas, M. J.; Edmonds, C. G.; McCloskey, J. A. (1987). "Identification of 12-keto-5,8,10-heptadecatrienoic acid as an arachidonic acid metabolite produced by human HL-60 leukemia cells". Biochemical Pharmacology. 36 (11): 1799–805. doi:10.1016/0006-2952(87)90241-3. PMID   3107571.
  14. ↑ Höhl, W; Stahl, B; Mundkowski, R; Hofmann, U; Meese, C. O.; Kuhlmann, U; Schlegel, W (1993). "Mass determination of 15-hydroxyprostaglandin dehydrogenase from human placenta and kinetic studies with (5Z, 8E, 10E, 12S)-12-hydroxy-5,8,10-heptadecatrienoic acid as substrate". European Journal of Biochemistry. 214 (1): 67–73. doi: 10.1111/j.1432-1033.1993.tb17897.x . PMID   8508808.
  15. ↑ Hofmann, U; Seefried, S; Meese, C. O.; Mettang, T; Hübel, E; Kuhlmann, U (1990). "Measurement of 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid and its metabolite 12-oxo-5Z,8E,10E-heptadecatrienoic acid in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry". Analytical Biochemistry. 189 (2): 244–8. doi:10.1016/0003-2697(90)90115-p. PMID   2281869.
  16. ↑ Campbell, P. B.; Tolson, T. A. (1988). "Modulation of human monocyte leukotactic responsiveness by thromboxane A2 and 12-hydroxyheptadecatrienoic acid (12-HHT)". Journal of Leukocyte Biology. 43 (2): 117–24. doi:10.1002/jlb.43.2.117. PMID   3422086. S2CID   6808683.
  17. 1 2 3 Okuno, T; Iizuka, Y; Okazaki, H; Yokomizo, T; Taguchi, R; Shimizu, T (2008). "12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2". The Journal of Experimental Medicine. 205 (4): 759–66. doi:10.1084/jem.20072329. PMC   2292216 . PMID   18378794.
  18. ↑ Ruf, A; Mundkowski, R; Siegle, I; Hofmann, U; Patscheke, H; Meese, C. O. (1998). "Characterization of the thromboxane synthase pathway product 12-oxoheptadeca-5(Z)-8(E)-10(E)-trienoic acid as a thromboxane A2 receptor antagonist with minimal intrinsic activity". British Journal of Haematology. 101 (1): 59–65. doi: 10.1046/j.1365-2141.1998.00669.x . PMID   9576182. S2CID   39982498.
  19. ↑ Yokomizo, T; Kato, K; Terawaki, K; Izumi, T; Shimizu, T (2000). "A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders". The Journal of Experimental Medicine. 192 (3): 421–32. doi:10.1084/jem.192.3.421. PMC   2193217 . PMID   10934230.
  20. 1 2 3 Tager, A. M.; Luster, A. D. (2003). "BLT1 and BLT2: The leukotriene B(4) receptors". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 69 (2–3): 123–34. doi:10.1016/s0952-3278(03)00073-5. PMID   12895595.
  21. ↑ Yokomizo, T; Kato, K; Hagiya, H; Izumi, T; Shimizu, T (2001). "Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2". Journal of Biological Chemistry. 276 (15): 12454–9. doi: 10.1074/jbc.M011361200 . PMID   11278893.
  22. 1 2 3 4 5 Yokomizo, T (2015). "Two distinct leukotriene B4 receptors, BLT1 and BLT2". Journal of Biochemistry. 157 (2): 65–71. doi: 10.1093/jb/mvu078 . PMID   25480980.
  23. ↑ Bäck, M; Powell, W. S.; Dahlén, S. E.; Drazen, J. M.; Evans, J. F.; Serhan, C. N.; Shimizu, T; Yokomizo, T; Rovati, G. E. (2014). "Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7". British Journal of Pharmacology. 171 (15): 3551–74. doi:10.1111/bph.12665. PMC   4128057 . PMID   24588652.
  24. ↑ Anwar, Y; Sabir, J. S.; Qureshi, M. I.; Saini, K. S. (2014). "5-lipoxygenase: A promising drug target against inflammatory diseases-biochemical and pharmacological regulation". Current Drug Targets. 15 (4): 410–22. doi:10.2174/1389450114666131209110745. PMID   24313690.
  25. ↑ Fourie, A. M. (2009). "Modulation of inflammatory disease by inhibitors of leukotriene A4 hydrolase". Current Opinion in Investigational Drugs. 10 (11): 1173–82. PMID   19876785.
  26. ↑ Hicks, A; Monkarsh, S. P.; Hoffman, A. F.; Goodnow Jr, R (2007). "Leukotriene B4 receptor antagonists as therapeutics for inflammatory disease: Preclinical and clinical developments". Expert Opinion on Investigational Drugs. 16 (12): 1909–20. doi:10.1517/13543784.16.12.1909. PMID   18042000. S2CID   33906245.
  27. ↑ Miyata, A; Yokoyama, C; Ihara, H; Bandoh, S; Takeda, O; Takahashi, E; Tanabe, T (1994). "Characterization of the human gene (TBXAS1) encoding thromboxane synthase". European Journal of Biochemistry. 224 (2): 273–9. doi: 10.1111/j.1432-1033.1994.00273.x . PMID   7925341.
  28. ↑ Ryu, H. C.; Kim, C; Kim, J. Y.; Chung, J. H.; Kim, J. H. (2010). "UVB radiation induces apoptosis in keratinocytes by activating a pathway linked to "BLT2-reactive oxygen species"". Journal of Investigative Dermatology. 130 (4): 1095–106. doi: 10.1038/jid.2009.436 . PMID   20090768.
  29. ↑ Lee, J. W.; Ryu, H. C.; Ng, Y. C.; Kim, C; Wei, J. D.; Sabaratnam, V; Kim, J. H. (2012). "12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity". Experimental & Molecular Medicine. 44 (6): 378–86. doi:10.3858/emm.2012.44.6.043. PMC   3389076 . PMID   22391335.
  30. 1 2 Matsunaga, Y; Fukuyama, S; Okuno, T; Sasaki, F; Matsunobu, T; Asai, Y; Matsumoto, K; Saeki, K; Oike, M; Sadamura, Y; Machida, K; Nakanishi, Y; Kubo, M; Yokomizo, T; Inoue, H (2013). "Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia". The FASEB Journal. 27 (8): 3306–14. doi:10.1096/fj.12-217000. PMID   23603839. S2CID   5595069.
  31. ↑ Singh, R. K.; Tandon, R; Dastidar, S. G.; Ray, A (2013). "A review on leukotrienes and their receptors with reference to asthma". Journal of Asthma. 50 (9): 922–31. doi:10.3109/02770903.2013.823447. PMID   23859232. S2CID   11433313.
  32. ↑ Watanabe, M; Machida, K; Inoue, H (2014). "A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung". Expert Review of Respiratory Medicine. 8 (4): 381–3. doi: 10.1586/17476348.2014.908715 . PMID   24742066. S2CID   33252079.
  33. 1 2 Liu, M; Saeki, K; Matsunobu, T; Okuno, T; Koga, T; Sugimoto, Y; Yokoyama, C; Nakamizo, S; Kabashima, K; Narumiya, S; Shimizu, T; Yokomizo, T (2014). "12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor". The Journal of Experimental Medicine. 211 (6): 1063–78. doi:10.1084/jem.20132063. PMC   4042643 . PMID   24821912.
  34. ↑ Kaushal, M; Gopalan Kutty, N; Mallikarjuna Rao, C (2007). "Wound healing activity of NOE-aspirin: A pre-clinical study". Nitric Oxide. 16 (1): 150–6. doi:10.1016/j.niox.2006.07.004. PMID   16978891.
  35. ↑ Gus-Brautbar, Y; Panigrahy, D (2014). "Time heals all wounds--but 12-HHT is faster". The Journal of Experimental Medicine. 211 (6): 1008. doi:10.1084/jem.2116insight1. PMC   4042644 . PMID   24890114.
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