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12-Hydroxyheptadecatrienoic acid
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12-Hydroxyheptadecatrienoic acid
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. 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. 12-HHT was discovered and structurally defined in 1973 by Paulina Wlodawer, Bengt Samuelsson, and Mats Hamberg. It was identified as a product of arachidonic acid metabolism made by microsomes isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT 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.
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. 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. 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.
Various cytochrome P450 enzymes (e.g. CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2S1, and CYP3A4) metabolize PGG2 and PGH2 to 12-HHT and MDA. 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. 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. 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.
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). 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.
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.
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 prostaglandin I2 (PGI2 or prostacyclin), a powerful inhibitor of platelet activation and stimulator of vasodilation (see Prostacyclin synthase). 12-HHT did not, however, alter arachidonic acid metabolism in human platelets. Shortly thereafter, 12-HHT was reported to inhibit the chemotaxis-blocking effect of a human monocyte-derived factor on human monocytes. 12-Oxo-HT, the immediate metabolite of 12-HHT, was reported to stimulate the chemotasis of human neutrophils 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. These studies were largely overlooked; in 1998 and 2007 publications, for example, 12-HHT was regarded as either inactive or without significant biological activity. Nonetheless, this early work suggested that 12-HHT may serve as a contributor to monocyte- and neutrophil-based inflammatory responses, and that 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: 12-oxo-HT 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. 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.
Leukotriene B4 (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 B44 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. 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). 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. 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. 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. BLT2 may ultimately prove to have binding specificity for a similarly broad range of agents.
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12-Hydroxyheptadecatrienoic acid
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. 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. 12-HHT was discovered and structurally defined in 1973 by Paulina Wlodawer, Bengt Samuelsson, and Mats Hamberg. It was identified as a product of arachidonic acid metabolism made by microsomes isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT 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.
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. 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. 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.
Various cytochrome P450 enzymes (e.g. CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2S1, and CYP3A4) metabolize PGG2 and PGH2 to 12-HHT and MDA. 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. 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. 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.
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). 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.
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.
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 prostaglandin I2 (PGI2 or prostacyclin), a powerful inhibitor of platelet activation and stimulator of vasodilation (see Prostacyclin synthase). 12-HHT did not, however, alter arachidonic acid metabolism in human platelets. Shortly thereafter, 12-HHT was reported to inhibit the chemotaxis-blocking effect of a human monocyte-derived factor on human monocytes. 12-Oxo-HT, the immediate metabolite of 12-HHT, was reported to stimulate the chemotasis of human neutrophils 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. These studies were largely overlooked; in 1998 and 2007 publications, for example, 12-HHT was regarded as either inactive or without significant biological activity. Nonetheless, this early work suggested that 12-HHT may serve as a contributor to monocyte- and neutrophil-based inflammatory responses, and that 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: 12-oxo-HT 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. 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.
Leukotriene B4 (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 B44 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. 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). 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. 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. 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. BLT2 may ultimately prove to have binding specificity for a similarly broad range of agents.
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