13-Hydroxyoctadecadienoic acid

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13-Hydroxyoctadecadienoic acid
Names
Preferred IUPAC name
(9Z,11E,13S)-13-Hydroxyoctadeca-9,11-dienoic acid
Other names
13(S)-HODE, 13S-HODE
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C18H32O3/c1-2-3-11-14-17(19)15-12-9-7-5-4-6-8-10-13-16-18(20)21/h7,9,12,15,17,19H,2-6,8,10-11,13-14,16H2,1H3,(H,20,21)/b9-7-,15-12+/t17-/m0/s1
    Key: HNICUWMFWZBIFP-IRQZEAMPSA-N
  • 9Z,11E,13R: InChI=1S/C18H32O3/c1-2-3-11-14-17(19)15-12-9-7-5-4-6-8-10-13-16-18(20)21/h7,9,12,15,17,19H,2-6,8,10-11,13-14,16H2,1H3,(H,20,21)/b9-7-,15-12+/t17-/m1/s1
  • 9E,11E: CCCCCC(/C=C/C=C/CCCCCCCC(=O)O)O
  • 9Z,11E,13S: CCCCC[C@@H](/C=C/C=C\CCCCCCCC(=O)O)O
  • 9Z,11E,13R: CCCCC[C@H](/C=C/C=C\CCCCCCCC(=O)O)O
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).

13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE). The production of 13(S)-HODE is often accompanied by the production of its

cis-trans
(i.e., 9E,11E) isomers viz., 13(S)-hydroxy-9E,11E-octadecadienoic acid (13(S)-EE-HODE) and 13(R)-hydroxy-9E,11E-octadecadienoic acid (13(R)-EE-HODE). Studies credit 13(S)-HODE with a range of clinically relevant bioactivities; recent studies have assigned activities to 13(R)-HODE that differ from those of 13(S)-HODE; and other studies have proposed that one or more of these HODEs mediate physiological and pathological responses, are markers of various human diseases, and/or contribute to the progression of certain diseases in humans. Since, however, many studies on the identification, quantification, and actions of 13(S)-HODE in cells and tissues have employed methods that did not distinguish between these isomers, 13-HODE is used here when the actual isomer studied is unclear.

A similar set of 9-Hydroxyoctadecadienoic acid (9-HODE) metabolites (i.e., 9(S)-HODE), 9(R)-HODE, 9(S)-EE-HODE), and 9(R)-EE-HODE) occurs naturally and particularly under conditions of oxidative stress forms concurrently with the 13-HODEs; the 9-HODEs have overlapping and complementary but not identical activities with the 13-HODEs. Some recent studies measuring HODE levels in tissue have lumped the four 9-HODEs with the four 13-HODEs to report only on total HODEs (tHODEs). tHODEs have been proposed to be markers for certain human diseases. Other studies have lumped together the 9-(S), 9(R), 13 (S)-, and 13(R)-HODEs along with the two ketone metabolites of these HODEs, 13-oxoODE (13-oxo-9Z,12E-octadecadienoic acid) and 9-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 13-HODEs

15-Lipoxygenase 1

15-lipoxygenase 1 (

15-hydroxyicosatetraenoic acid), actually prefers as its substrate the 18 carbon polyunsaturated fatty acid, linoleic acid, over arachidonic acid, converting it to 13-hydroperoxy-9Z,11E-octadecadienoic acid (13-HpODE).[1][2] The enzyme acts in a highly stereospecific manner, forming 13(S)-hydroperoxy-9Z,11E-octadecadienoic acid (13(S)-HpODE) but comparatively little or no 13(R)-hydroperoxy-9Z,11E-octadecadienoic acid (13(R)-HpODE) -.[3][4] In cells, 13(S)-HpODE is rapidly reduced by peroxidases to 13(S)-HODE.[1][5] ALOX15 is fully capable of metabolizing the linoleic acid that is bound to phospholipid[6] or cholesterol[7]
to form 13(S)-HpODE-bound phospholipids and cholesterol that are rapidly converted to their corresponding 13(S)-HODE-bound products.

15-lipoxygenase 2

15-lipoxygenase type 2 (ALOX15B) strongly prefers arachidonic acid over linoleic acid and in consequence is relatively poor in metabolizing linoleic acid to 13(S)-HpODE (which is then converted to 13(S)-HODE) compared to 15-lipoxygenase 1;[8] nonetheless, it can contribute to the production of these metabolites.[2][9]

Cyclooxygenases 1 and 2

cyclooxygenase 2 (COX-2) metabolize linoleic acid to 13(S)-HODE with COX-2 exhibiting a higher preference for linoleic acid and therefore producing far more of this product than its COX-1 counterpart;[10] consequently, COX-2 appears to be the principle COX making 13(S)-HODE in cells expressing both enzymes.[11] Concurrently with their production of 13(S)-HODE, these enzymes also produce smaller amounts of 9(R)-HODE.[12][11]

Cytochrome P450

microsomal enzymes metabolize linoleic acid to a mixture of 13-HODEs and 9-HODEs; these reactions produce racemic mixtures in which the R stereoisomer predominates, for instance by a R/S ratio of 80%/20% for both 13-HODE and 9-HODE in human liver microsomes.[13][14][15]

Free radical and singlet oxygen oxidations

Free radical and singlet oxygen oxidations of linoleic acid to generate 13-HpODEs, 9-HpODEs, 13-HODEs, and 9-HODEs; these non-enzymatic reactions produce or are suspected but not proven to produce approximately equal amounts of their S and R stereoisomers.[16][17][18] Free radical oxidations of linoleic acid also produce 13-EE-HODE, 9-hydroxy-10E,12-E-octadecadienoic acid, 9-hydroxy-10E,12-Z-octadecadienoic acid, and 11-hydroxy-9Z,12Z-octadecadienoic acid while singlet oxygen attacks on linoleic acid produce (presumably) racemic mixtures of 9-hydroxy-10E,12-Z-octadecadienoic acid, 10-hydroxy-8E,12Z-octadecadienoic acid, and 12-hydroxy-9Z-13-E-octadecadienoic acid.[19] 4-Hydroxynonenal (i.e. 4-hydroxy-2E-nonenal or HNE) is also a peroxidation product of 13-HpODE.[20] Since oxidative stress commonly produces both free radicals and singlet oxygen, most or all of these products may form together in tissues undergoing oxidative stress. Free radical and singlet oxygen oxidations of linoleic acid produce a similar set of 13-HODE metabolites (see 9-Hydroxyoctadecadienoic acid). Studies attribute these oxidations to be major contributors to 13-HODE production in tissues undergoing oxidative stress including in humans sites of inflammation, steatohepatitis, cardiovascular disease-related atheroma plaques, neurodegenerative disease, etc. (see oxidative stress).[21][19]

Metabolism of 13(S)-HODE

Like most polyunsaturated fatty acids and mono-hydroxyl polyunsaturated fatty acids, 13(S)-HODE is rapidly and quantitatively incorporated into

phospholipids;[22] the levels of 13(S)-HODE esterified to the sn-2 position of phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine in human psoriasis lesions are significantly lower than those in normal skin; this chain shortening pathway may be responsible for inactivating 13(S)-HODE.[23] 13(S)-HODE is also metabolized by peroxisome-dependent β-oxidations to chain-shortened 16-carbon, 14-carbon, and 12-carbon products which are released from the cell;[24]
this chain-shortening pathway may serve to inactive and dispose of 13(S)-HODE.

13(S)-HODE is oxidized to 13-oxo-9Z,11E-octadecadienoic acid (13-oxo-HODE or 13-oxoODE) by a

glutathione transferase.[35][36] Since this conjugate may be rapidly exported from the cell and has not yet been characterized for biological activity, it is not clear if this transferase reaction serves any function beyond removing 13-oxo-ODE from the cell to limit its activity.[34]

Activities

Stimulation of peroxisome proliferator-activated receptors

13-HODE, 13-oxoODE, and 13-EE-HODE (along with their 9-HODE counterparts) directly activate

peroxisome proliferator-activated receptor beta (PPARβ) in a model cell system; 13-HODE (and 9-HODE) are also proposed to contribute to the ability of oxidized low-density lipoprotein (LDL) to activate PPARβl: LDL containing phospholipid-bound 13-HODE (and 9-HODE) is taken up by the cell and then acted on by phospholipases to release the HODEs which in turn directly activate PPARβl.[40]

Stimulation of TRPV1 receptor

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[41] 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).

Stimulation of GPR132 receptor

13(S)-HpODE, and 13(S)-HODE directly activate human (but not mouse) GPR132 (G protein coupled receptor 132, also termed G2A) in Chinese hamster ovary cells made to express these receptors; they are, however, far weaker GPR132 activators than 9(S)-HpODE or 9(S)-HODE.[42][43] GPR132 was initially described as a pH sensing receptor; the role(s) of 13(S)-HpODE and 13(S)-HODE as well as 9(S)-HpODE, 9(S)HODE, and a series or GPR132-activating arachidonic acid hydroxy metabolites (i.e. HETEs) in activating G2A under the physiological and pathological conditions in which G2A is implicated (see GPR132 for a lists 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.

Involvement in mitochondria degradation

In the maturation of the red blood cell lineage (see

erythrocytes in rabbits, the mitochondria accumulate phospholipid-bound 13(S)-HODE in their membranes due to the action of a lipoxygenase which (in rabbits, mice, and other sub-primate vertebrates) directly metabolizes linoleic acid-bound phospholipid to 13(S)-HpODE-bound phospholipid which is rapidly reduced to 13(S)-HODE-bound phospholipid.[44] It is suggested that the accumulation of phospholipid-bound 13(S)-HpODE and/or 13(S)-HODE is a critical step in rendering mitochondria more permeable thereby triggering their degradation and thence maturation to erythrocytes.[44][45] However, functional inactivation of the phospholipid-attacking lipoxygenase gene in mice does not cause major defects in erythropoiesis.[46] It is suggested that mitochondrial degradation proceeds through at least two redundant pathways besides that triggered by lipoxygenase-dependent formation of 13(S)-HpODE- and 13(S)-HODE-bound phospholipids viz., mitochondrial digestion by autophagy and mitochondrial exocytosis.[47] In all events, formation of 13(S)-HODE bound to phospholipid in mitochondrial membranes is one pathway by which they become more permeable and thereby subject to degradation and, as consequence of their release of deleterious elements, to cause cell injury.[48]

Stimulation of blood leukocytes

13-HODE (and 9-HODE) are moderately strong stimulators of the directed migration (i.e. chemotaxis) of cow and human neutrophils in vitro[49] whereas 13(R)-HODE (and 9(R)-HODE, and 9(S)-HODE) are weak stimulators of the in vitro directed migration of the human cytotoxic and potentially tissue-injuring lymphocytes, i.e. natural killer cells.[50] These effects may contribute to the pro-inflammatory and tissue-injuring actions ascribed to 13-HODEs (and 9-HODEs).

Involvement in human diseases

Atherosclerosis

In

Statins, which are known to suppress cholesterol synthesis by inhibiting an enzyme in the cholesterol synthesis pathway, 3-hydroxy-3-methyl-glutaryl-CoA reductase HMG-CoA reductase, are widely used to prevent atherosclerosis and atherosclerosis-related diseases. Statins also inhibit PPARγ in human macrophages, vascular endothelial cells, and smooth muscle cells; this action may contribute to their anti-atherogenic effect.[60]

Asthma

In guinea pigs, 13(S)-HODE, when injected intravenously, causes a narrowing of lung airways and, when inhaled as an aerosol, mimics the asthmatic hypersensitivity to agents that cause

leukocyte.[64] The mechanism responsible for 13-HODE's impact on airway epithelial cells may involve its activation of the TRPV1 receptor (see previous section on TRPV1): this receptor is highly expressed in mouse and human airway epithelial cells and in Beas 2B human airway epithelial cells and, furthermore, suppression of TRPV1 expression as well as a TPRV1 receptor inhibitor (capsazepan) block mouse airway responses to 13(S)-HODE.[48]
While much further work is needed, these pre-clinical studies allow that 13(S)-HODE, made at least in part by eosinophils and operating through TRPV1, may be responsible for the airways damage which occurs in the more severe forms of asthma and that pharmacological inhibitors of TRPV1 may eventually proved to be useful additions to the treatment of asthma.

Cancer

Colon cancer

polyps which have a high risk of turning cancerous.[65] One of the abnormalities found in the APC disease is progressive reductions in 15-lipoxygenase 1 along with its product, 13-HODE (presumed but not unambiguously shown to be the S stereoisomer) as the colon disease advances from polyp to malignant stages; 15-HETE, 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase-2, and selected metabolites of the latter lipoxygenases show no such association.[66][67][68] Similarly selective reductions in 15-lipoxygenase 1 and 13-HODE occur in non-hereditary colon cancer.[69][70][66] 13(S)-HODE inhibits the proliferation and causes the death (apoptosis) of cultured human colon cancer cells.[55][69][71][70] Animal model studies also find that the 15-lipoxygenase 1 / 13-HODE axis inhibits the development of drug-induced colon cancer as well as the growth of human colon cancer cell explants.[67]
These results suggest that 15-lipoxygenase 1 and its 13(S)-HODE product are factors in promoting genetically-associated and -non-associated colon cancers; they function by contributing to the suppression of the development and/or growth of this cancer and when reduced or absent allow its unrestrained, malignant growth.

Breast cancer

13(S)-HODE stimulates the proliferation of human

xenografts to grow in mice.;[74] and among a series of 10 polyunsaturated fatty acid metabolites quantified in human breast cancer tissue, only 13-HODE (stereoisomer not defined) was significantly elevated in rapidly growing, compared to slower growing, cancers.[72]
The results of these studies suggest that 13(S)-HODE may act to promote the growth of breast cancer in humans.

Prostate cancer

15-LOX 1 is overexpressed in prostate cancerous compared to non-cancerous prostate tissue and the levels of its expression in cultured various human prostate cancer cell lines correlates positively with their rates of proliferation and increases the proliferation response of prostate cancer cells to

Gleason score; and overexpressed 15-LOX 1 appears to not only increase prostate cancer cell proliferation, but also promotes its cell survival by stimulating production and of insulin-like growth factor 1 and possibly altering the Bcl-2 pathway of cellular apoptosis as well as increases prostate tumor vascularization and thereby metastasis by stimulating production of vascular endothelial growth factor. These 15-LOX 1 effects appear due to the enzyme's production of 13(S)-HODE.[75][76][77] The 15-LOX 1/13(S)-HODE axis also promotes the growth of prostate cancer in various animal models.[78][79] In one animal model the pro-growth effects of 15-LOX 1 were altered by dietary targeting: increases in dietary linoleic acid, an omega-6 fatty acid, promoted while increases in dietary stearidonic acid, an omega-3 fatty acid reduced the growth of human prostate cancer explants.[80] These effects could be due to the ability of the linoleic acid diet to increase the production of the 15-Lox 1 metabolite, 13-HODE,[80] and the ability of the stearidonic acid to increase the production of docosahexaenoic acid and the 15-LOX-1 metabolites of docosahexaenoic acid, 17S-hydroperoxy-docosa-hexa-4Z,7Z,10Z,13 Z,15E,19Z-enoate(17-HpDHA, 17S-hydroxy-docosahexa-4Z,7Z,10Z,13Z,15E,19Z-enoate(17-HDHA), 10S,17S-dihydroxy-docosahexa-4Z,7Z,11E,13Z,15E,19Z-enoate(10,17-diHDHA, protectin DX), and 7S,17S-dihydroxy-docsahexa-4Z,8E,10Z,13Z,15E,19Z-enoate(7,17-diHDHA, protectin D5), all of which are inhibitors of cultured human prostate cancer cell proliferation.[81][82][83]

Markers for disease

13-HODE levels are elevated, compared to appropriate controls, in the low density lipoproteins isolated from individuals with

9-hydroxyoctadecadienoic acid section on 9-HODEs as markers of disease involving oxidative stress for further details. These studies suggest that high levels of the HODEs may be useful to indicate the presence and progression of the cited diseases. Since, however, the absolute values of HODEs found in different studies vary greatly, since HODE levels vary with dietary linoleic acid intake, since HODEs may form during the processing of tissues, and since abnormal HODE levels are not linked to a specific disease, the use of these metabolites as markers has not attained clinical usefulness.[21][91][92][19] HODE markers may find usefulness as markers of specific disease, type of disease, and/or progression of disease when combined with other disease markers.[19][93]

References

  1. ^
    PMID 3920219
    .
  2. ^
    PMID 18570379
    .
  3. PMID 2735926
    .
  4. PMID 8334154
    .
  5. PMID 12432923
    .
  6. PMID 23203133
    .
  7. ^ Cholesterol at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  8. PMID 9177185
    .
  9. PMID 19645454
    .
  10. PMID 7642610
    .
  11. ^
    PMID 8875957
    .
  12. PMID 6768399
    .
  13. PMID 6431911
    .
  14. PMID 8443245
    .
  15. PMID 23006841
    .
  16. PMID 6100997
    .
  17. PMID 9593808
    .
  18. PMID 15720142
    .
  19. ^
    PMID 25766928
    .
  20. S2CID 6062445
    .
  21. ^
    PMID 22959954
    .
  22. PMID 8169529
    .
  23. S2CID 25517644
    .
  24. PMID 10191294
    .
  25. PMID 2020745
    .
  26. PMID 8242849
    .
  27. PMID 1998735
    .
  28. PMID 2112367
    .
  29. PMID 11355856
    .
  30. ^
    PMID 19843694
    .
  31. PMID 17604003
    .
  32. PMID 26186333
    .
  33. ^
    PMID 22505276
    .
  34. ^
    PMID 12432937
    .
  35. PMID 8649225
    .
  36. PMID 10521706
    .
  37. ^
    S2CID 7573475
    .
  38. PMID 19172745
    .
  39. PMID 19336916
    .
  40. S2CID 85113031
    .
  41. PMID 22861649
    .
  42. PMID 19063986
    .
  43. PMID 19286662
    .
  44. ^
    PMID 2104842
    .
  45. S2CID 4366265
    .
  46. PMID 8798642
    .
  47. PMID 26216303
    .
  48. ^
    PMID 23443229
    .
  49. PMID 2020743
    .
  50. S2CID 37940201
    .
  51. PMID 8195716
    .
  52. PMID 7615823
    .
  53. PMID 12618275
    .
  54. PMID 9062346
    .
  55. ^
    PMID 25035111
    .
  56. ^
    PMID 23148161
    .
  57. ^
    S2CID 4062623
    .
  58. PMID 10772649
    .
  59. PMID 11385507
    .
  60. PMID 25529449
    .
  61. PMID 7622761
    .
  62. ^
    PMID 18714027
    .
  63. PMID 20673980
    .
  64. PMID 8880897
    .
  65. PMID 25955461
    .
  66. ^
    PMID 20570882
    .
  67. ^
    PMID 22960430
    .
  68. PMID 25316652
    .
  69. ^
    PMID 10506115
    .
  70. ^
    PMID 14643174
    .
  71. PMID 12909723
    .
  72. ^
    PMID 23658799
    .
  73. PMID 9070230
    .
  74. S2CID 22711432
    .
  75. S2CID 21497252
    .
  76. PMID 12189136
    .
  77. PMID 15068670
    .
  78. PMID 16820097
    .
  79. PMID 16997127
    .
  80. ^
    PMID 19568414
    .
  81. PMID 15623603
    .
  82. PMID 23029040
    .
  83. PMID 23066085
    .
  84. PMID 9219348
    .
  85. PMID 25794249
    .
  86. PMID 24343898
    .
  87. S2CID 42972163
    .
  88. PMID 20460374
    .
  89. PMID 20631297
    .
  90. S2CID 23418993
    .
  91. PMID 23341691
    .
  92. PMID 23541987
    .
  93. PMID 24559154
    .
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