12-Hydroxyheptadecatrienoic acid

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12-Hydroxyheptadecatrienoic acid
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 Edit this at Wikidata
IUPHAR/BPS
  • 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

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.

Production

Primary source

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

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

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

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

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

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

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

References

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