9-Hydroxyoctadecadienoic acid
This article may be confusing or unclear to readers. (August 2015) |
Names | |
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Preferred IUPAC name
(9S,10E,12Z)-9-Hydroxyoctadeca-10,12-dienoic acid | |
Other names
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Identifiers | |
3D model (
JSmol ) |
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ChemSpider | |
ECHA InfoCard
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100.230.886 |
PubChem CID
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UNII | |
CompTox Dashboard (EPA)
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Properties | |
C18H32O3 | |
Molar mass | 296.451 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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9-Hydroxyoctadecadienoic acid (or 9-HODE) has been used in the literature to designate either or both of two
A similar set of 13-Hydroxyoctadecadienoic acid (13-HODE) metabolites (13(S)-HODE), 13(R)-HODE, 13(S)-EE-HODE), and 13(R)-EE-HODE) also occurs naturally and, again particularly under conditions of oxidative stress, may form concurrently with 9-HODEs; these 13-HODEs also have overlapping and complementary but not identical activities with the 9-HODEs. Some recent studies measuring HODE levels in tissue have lumped the four 9-HODEs and four 13-HODEs together to report only on total HODEs (tHODEs): tHODEs have been proposed to be markers for certain human disease. Other recent studies have lumped together the 9-(S), 9(R), 13 (S)-, and 13(R)-HODE along with the two ketone metabolites of these HODEs, 9-oxoODE (9-oxo-10(E),12(Z)-octadecadienoic acid) and 13-oxoODE, reporting only on total OXLAMs (oxidized linoleic acid metabolites); the OXLAMs have been implicated in working together to signal for pain perception.
Pathways making 9-HODEs
Cyclooxygenases 1 and 2
The enzymes
Cytochrome P450
Free-radical and singlet-oxygen oxidations
Mouse 8(S)-lipoxygenase
The murine homolog of human 15(S)-lipoxygenase-2 (ALOX15B), 8(S)-lipoxygenase, while preferring arachidonic acid over linoleic acid, metabolizes linoleic acid predominantly to (9(S)-HpODE, which in tissues and cells is rapidly reduced to 9(S)-HODE.[15][16] However, ALOX15B, similar to human 15-lipoxygenase-1 (ALOX15), metabolizes linoleic acid to 13(S)-HODE but not to 9(S)-HODEs.[17][18]
Metabolism
Like most unsaturated fatty acids, the 9-HODEs formed in cells are incorporated into cellular
9-HODE may be further metabolized to 9-oxo-10(E),12(Z)-octadecadienoic acid (9-oxoODE or 9-oxo-ODE), possibly by the same hydroxy-fatty-acid dehydrogenase which metabolizes other hydroxy fatty acids, such as 13-HODE, to their oxo derivatives.[24]
Direct actions
9-HODE, 9-oxoODE, and 9-EE-HODE (along with their 13-HODE counterparts) directly activate
13(S)-HODE, 13(R)-HODE and 13-oxoODE, along with their 9-HODE counterparts, also act on cells through TRPV1. TRPV1 is the transient receptor potential cation channel subfamily V member 1 receptor (also termed capsaicin receptor or vanilloid receptor 1). These 6 HODEs, dubbed, oxidized linoleic acid metabolites (OXLAMs), individually but also and possibly to a greater extent when acting together, stimulate TRPV1-dependent responses in rodent neurons, rodent and human bronchial epithelial cells, and in model cells made to express rodent or human TRPV1. This stimulation appears due to a direct interaction of these agents on TRPV1 although reports disagree on the potencies of the (OXLAMs) with, for example, the most potent OXLAM, 9(S)-HODE, requiring at least 10 micromoles/liter[29] or a more physiological concentration of 10 nanomoles/liter[30] to activate TRPV1 in rodent neurons. The OXLAM-TRPV1 interaction is credited with mediating pain sensation in rodents (see below).
9(S)-HODE and with progressively lesser potencies 9(S)-HpODE, a racemic mixture of 9-HODE, 13(S)-HpODE, and 13(S)-HODE directly activate human (but not mouse) GPR132 (i.e. G protein coupled receptor 132 or G2A) in Chinese hamster ovary cells made to express these receptors; 9(S)-HODE was also a more potent stimulator of human G2A than a series of mono-hydroxy arachidonic acid metabolites.[31][32] GPR132 was initially described as a pH sensing receptor; the role(s) of 9-HODEs as well as other linoleic and arachidonic acid metabolites in activating GPR132 under the physiological and pathological conditions in which it is implicated to be involved(see (see GPR132 for a listing of these conditions) have not yet been determined. This determination, as it might apply to humans, is made difficult by the inability of these HODEs to activate rodent GPR132 and therefore to be analyzed in rodent models.
Biological and clinical relevancy
As markers of disease involving oxidative stress
Various measurements of tissue and blood levels of
Studies find that 1) 9(S)-HODE (and 13(S)-HODE) levels are elevated in the plasma of older patients with early-stage
Some of the studies cited above have suggested that 9-HODEs, 13-HODEs, their hydroperoxy counterparts, and/or their oxo counterparts contribute mechanistically to these oxidative-stress-related diseases. That is, the free radical oxidation of linoleic acid makes these products which then proceed to contribute to the tissue injury, DNA damage, and/or systemic dysfunctions that characterize the diseases.[42][43][44][45][46] Furthermore, certain of these HODE-related products may serve as signals to activate pathways that combat the reactive oxygen species and in this and other ways the oxidative stress. It remains unclear whether or not the HODEs and their counterparts promote, dampen, or merely reflect oxidative-stress-related diseases.
As mediators of pain perception
9(S)-HODE, 9(R)-HODE, and 9-oxoODE, along with the other OXLAMs, appear to act through the TRPV1 receptor (see above section on Direct actions) mediate the perception of acute and chronic pain induced by heat, UV light, and inflammation in the skin of rodents.[30][47][48][49][50] These studies propose that the OXLAM-TRPV1 circuit (with 9(S)-HODE being the most potent TRPV1-activating OXLAM) similarly contributes to the perception of pain in humans.
As contributors to atherosclerosis
9-HODEs, 13-HODEs, and
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