9-Hydroxyoctadecadienoic acid

9-Hydroxyoctadecadienoic acid
Names
IUPAC name
(9S,10E,12Z)-9-Hydroxy-10,12-octadecadienoic acid
Other names
α-Dimorphecolic acid
Identifiers
73543-67-6
3D model (Jmol) Interactive image
ECHA InfoCard 100.230.886
Properties
C18H32O3
Molar mass 296.45 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

9-Hydroxyoctadecadienoic acid (9-hydroxy-10(E),12(Z)-octadecadienoic acid or 9-HODE) has been used in the literature to designate either or both of two stereoisomer metabolites of the essential fatty acid, linoleic acid: 9(S)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(S)-HODE) and 9(R)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(R)-HODE); these two metabolites differ in having their hydroxy residues in the S or R configurations, respectively. The accompanying figure gives the structure for 9(S)-HETE. Two other 9-hydroxy linoleic acid derivatives occur in nature, the 10E,12E isomers of 9(S)-HODE and 9(R)-HODE viz., 9(S)-hydroxy-10E,12E-octadecadienoic acid (9(S)-EE-HODE) and 9(R)-hydroxy-10E,12E-octadecadienoic acid (13(R)-EE-HODE); these two derivatives have their double bond at carbon 12 in the E or trans configuration as opposed to the Z or cis configuration. The four 9-HODE isomers, particularly under conditions of oxidative stress, may form together in cells and tissues; they have overlapping but not identical biological activities and significances. Because many studies have not distinguished between the S and R stereoisomers and, particularly in identifying tissue levels, the two EE isomers, 9-HODE is used here when the isomer studied is unclear.

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 cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), which are best known for metabolizing arachidonic acid to prostaglandins, are also able to metabolize linoleic acid predominantly to 9(R)-hydroperoxy-10(E),12(Z)-octadecadienoic acid (i.e. 9(R)-HpODE)-HODE) and lesser amounts of 9(S)-hydroperoxy-10(E),12(Z)-octadecadienoic acid (i.e. 9(S)-HpODE); in cells and tissues, the two hydroperoxy metabolites are rapidly reduce to 9(R)-HODE and 9(S)-HODE, respectively.[1][2][3] COX-2 exhibits a greater preference for linoleic acid than does Cox-1 and is therefore credited with producing most of these products in cells expressing both COX enzymes.[2] The COXs also metabolize linoleic acid to 13(S)-hydroperoxy-octadecadionoic acid (13(S)-HpODE and lesser amounts of 13(R)-hydroperoxy-octadecadienoic acid (13(R)-HpODE, which are then rapidly reduced to 13(S)-HODE) and 13(R)-HODE; the two enzymes therefore metabolize linoleic acid predominantly to the R stereoisomer of 9-HODE and (S) stereoisomer of 13-HODE with the 13-HODE products predominating over the 9-HODE products.[1][2][4]

Cytochrome P450

Cytochrome P450 microsomal enzymes metabolize linoleic acid to a mixture of 9(S)-HpODE and 9(R)-HpODE which are subsequently reduced to their corresponding hydroxy products; these reactions produce racemic mixtures in which the R stereoisomer predominates, for instance by a R/S ratio of 80%/20% in human liver microsomes.[5][6][7] In cells and tissues, the cytochrome enzymes concurrently metabolize linoleic acid to 13(S)-HpODE and 13(R)-HpODE which are reduced to 13(S)-HODE and 13(R)-HODE in an R/S ratio similar to than of the 9-HODES, i.e. 80%/20%.[6]

Free radical and singlet oxygen oxidations

Oxidative stress in cells and tissues produces Free radical-induced and singlet oxygen-induced oxidations of linoleic acid to generate the various racemic mixtures of 9-HpODE and 9-HODE in non-enzymatic reactions that produce, or are suspected but not proven to produce, approximately equal amounts of their S and R stereoisomers.[8][9][10] These oxidations are credited with being the major contributors to 9-HODE and 13-HODE isomer production in tissues undergoing oxidative stress such as occurs in any tissue suffering inadequate blood flow, inflammation, or other serious insult, in liver steatohepatitis, in the atheroma plaques of cardiovascular disease, in nerve tissues of neurodegenerative diseases, and in the various tissues compromised by diabetes (see oxidative stress).[11][12] Free radical oxidation of linoleic acid produces racemic mixtures of 9-HODE and 9-EE-HODE; singlet oxygen attack on linoleic acid produces (presumably) racemic mixtures of 9-HODE, 10-hydroxy-8E,12Z-octadecadienoic acid, and 12-hydroxy-9Z-13-E-octadecadienoic acid.[13][14] Since free radical-induced and singlet oxygen-induced oxidations of linoleic acid produce a similar set of 13-HODE metabolites (see 13-Hydroxyoctadecadienoic acid), since both free radicals and singlet oxygen attack not only free linoleic acid but also linoleic acid bound to phospholipids, glycerides, cholesterol, and other lipids, and since free radical and singlet oxygen reactions may occur together, oxygen-stressed tissues often contain an array of free and lipid-bound 9-HODE and 13-HODE products. For example, laboratory studies find that 9-HODE and 9-EE-HODE (along with their 13-HODE counterparts) are found in the phospholipid and cholesterol components of low density lipoproteins that have been oxidized by human monocytes; the reaction appears due to the in situ free radical- and/or superoxide-induced oxidation of the lipoproteins.[15]

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.[16][17] However, ALOX15B, similar to human 15-lipoxygenase-1 (ALOX15), metabolizes linoleic acid to 13(S)-HODE but not to 9(S)-HODEs.[18][19]

Metabolism of 9-HODEs

Like most unsaturated fatty acids, the 9-HODEs formed in cells are incorporated into cellular phospholipids principally at the sn-2 position of the phospholipid (see Phospholipase A2);[20][21] since, however, the linoleic acid bound to cellular phospholipids is susceptible to non-enzymatic peroxidation and free radical attack,[22][23][24] the 9-HODEs in cellular phospholipids may also derive more directly from in situ oxidation. 9-HODE esterified to the sn-2 position of phosphatidylserine is subject to be released as free 9-HODE by the action of cytosolic (see phospholipase A2 section on cPLA2) and therefore may serve as a storage pool that is mobilized by cell stimulation.[25]

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.[26]

Direct actions of 9-HODEs

9-HODE, 9-oxoODE, and 9-EE-HODE (along with their 13-HODE counterparts) directly activate peroxisome proliferator-activated receptor gamma (PPARγ).[27][28][29] This activation appears responsible for the ability of 13-HODE (and 9-HODE) to induce the transcription of PPARγ-inducible genes in human monocytes as well as to stimulate the maturation of these cells to macrophages.[27] 13(S)-HODE (and 9(S)-HODE) also stimulate the activation of 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.[30]

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[31] or a more physiological concentration of 10 nanomoles/liter[32] 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.[33][34] 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 of 9-HODEs

9-HODEs as markers of disease involving oxidative stress

Various measurements of tissue and blood levels of reactive oxygen species have been used as markers of diseases in which these species are generated and may contribute to tissue injury and systemic disturbances; examples of such diseases include a wide range of neurological, cardiovascular, infectious, autoimmune, and genetic diseases (see oxidative stress). HODEs measurements have been evaluated as markers for many of these oxygen stress-related diseases. These measurements commonly use saponification methods to release HODEs bound by acylation to other molecules; they therefore measure not only free HODEs but also HODEs acylated to phospholipids, glycerides, cholesterol, and other lipids.

Studies find that 1) 9(S)-HODE (and 13(S)-HODE) levels are elevated in the plasma of older patients with early-stage cataracts compared to non-cataract subjects; 2) 9-HODE (and 13-HODE) are increased in the low density lipoproteins of patients with rheumatoid arthritis compared to healthy subjects as well as in the destructive but not normal bone tissue of the rheumatoid arthritic patients; 3) total HODEs (includes 9-HODE and 13-HODE stereoisomers) are higher in the plasma and liver of patients with hepatitis C and hepatitis B chronic viral infections as well as in the plasma and red blood cells of patients with Alzheimer's disease compared to healthy subjects; 4) 9-HODE and 9-oxoODE (as well as 13-HODE and 13-oxo-ODE) levels were elevated in the serum and/or pancreatic secretions of patients with pancreatitis compared to control subjects; 5) levels of the hydroperoxy precursors to 9-HODE and 13-HODE are elevated in the plasma and/or red blood cells of patients with Alzheimer's disease, atherosclerosis, diabetes, diabetic nephritis, non-alcoholic steatohepatitis, and alcoholic steatohepatitis compared to healthy subjects.[35][36][37][38][39][40][41] 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.[11][42][43][44] HODE markers may find usefulness as markers of specific disease, type of disease, and/or progression of disease when combined with other disease markers.[45][46]

9-HODEs as mediators of oxidative stress-related diseases

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.[47][48][49][50][51] 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.

9-HODEs 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.[52][53][54][55][56][57] 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 in humans.

9-HODEs as contributors to atherosclerosis

9-HODEs, 13-HODEs, and low density lipoprotein which has been oxidized so that it contains HODEs stimulate the expression of interleukin 1β mRNA in and its extracellular release from human peripheral blood monocyte-derived macrophages; interleukin 1β is implicated in the proliferation of smooth muscle cells that occurs in atherosclerosis and contributes to blood vessel narrowing.[58]

References

  1. 1 2 J Biol Chem. 1995 Aug 18;270(33):19330-6
  2. 1 2 3 J Invest Dermatol. 1996 Nov;107(5):726-32
  3. ↑ rch Biochem Biophys. 1998 Jan 15;349(2):376-80
  4. ↑ Prostaglandins. 1989 Aug;38(2):203-14
  5. ↑ Arch Biochem Biophys. 1984 Aug 15;233(1):80-7
  6. 1 2 Biochim Biophys Acta. 1993 Feb 24;1166(2-3):258-63
  7. ↑ Mol Pain. 2012 Sep 24;8:73. doi:10.1186/1744-8069-8-73
  8. ↑ Prog Lipid Res. 1984;23(4):197-221
  9. ↑ Biochim Biophys Acta. 1998 May 20;1392(1):23-40
  10. ↑ Chem Res Toxicol. 2005 Feb;18(2):349-56
  11. 1 2 Prostaglandins Leukot Essent Fatty Acids. 2012 Oct-Nov;87(4-5):135-41. doi:10.1016/j.plefa.2012.08.004
  12. ↑ J Oleo Sci. 2015;64(4):347-56. doi:10.5650/jos.ess14281
  13. ↑ Free Radic Biol Med. 2015 Feb;79:164-75. doi:10.1016/j.freeradbiomed.2014.12.004
  14. ↑ J Oleo Sci. 2015;64(4):347-56. doi:10.5650/jos.ess14281
  15. ↑ J Lipid Res. 1994 Sep;35(9):1570-82
  16. ↑ Mol Carcinog. 1999 Feb;24(2):108-17
  17. ↑ Oncogene. 2005 Feb 10;24(7):1174-87
  18. ↑ Eur J Biochem. 1999 Nov;266(1):83-93
  19. ↑ Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6148-52
  20. ↑ Exp Dermatol. 1993 Feb;2(1):38-4
  21. ↑ J Lipid Res. 1993 Sep;34(9):1473-82
  22. ↑ Free Radic Biol Med. 1995 Jun;18(6):1003-12
  23. ↑ Biochim Biophys Acta. 1999 May 18;1438(2):204-12
  24. ↑ Biochemistry. 2012 Dec 4;51(48):9736-50. doi:10.1021/bi301024e
  25. ↑ Biochemistry. 2012 Dec 4;51(48):9736-50. doi:10.1021/bi301024e
  26. ↑ Biomed Chromatogr. 2013 Apr;27(4):422-32. doi:10.1002/bmc.2809
  27. 1 2 Cell. 1998 Apr 17;93(2):229-40
  28. ↑ Nat Struct Mol Biol. 2008 Sep;15(9):924-31
  29. ↑ Biol Pharm Bull. 2009 Apr;32(4):735-40
  30. ↑ FEBS Lett. 2000 Apr 7;471(1):34-8
  31. ↑ Br J Pharmacol. 2012 Dec;167(8):1643-51. doi:10.1111/j.1476-5381.2012.02122.x
  32. ↑ Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18820-4. doi:10.1073/pnas.0905415106
  33. ↑ Prostaglandins Other Lipid Mediat. 2009 Sep;89(3-4):66-72. doi:10.1016/j.prostaglandins.2008.11.002
  34. ↑ J Biol Chem. 2009 May 1;284(18):12328-38. doi:10.1074/jbc.M806516200
  35. ↑ Chem Phys Lipids. 1997 May 30;87(1):81-9
  36. ↑ Z Naturforsch C. 1998 Nov-Dec;53(11-12):1061-71
  37. ↑ Eye (Lond). 2009 Jun;23(6):1464-8. doi:10.1038/eye.2008.281
  38. ↑ Neurobiol Aging. 2009 Feb;30(2):174-85. Epub 2007 Aug 3
  39. ↑ J Clin Biochem Nutr. 2013 Jan;52(1):9-16. doi:10.3164/jcbn.12-112
  40. ↑ J Lipid Res. 2010 Oct;51(10):3046-54. doi:10.1194/jlr.M007096
  41. ↑ Pancreas. 2012 May;41(4):518-22. doi:10.1097/MPA.0b013e31823ca306
  42. ↑ J Clin Biochem Nutr. 2013 Jan;52(1):9-16. doi:10.3164/jcbn.12-112
  43. ↑ Biochim Biophys Acta. 2014 Feb;1840(2):809-17. doi:10.1016/j.bbagen.2013.03.020
  44. ↑ J Oleo Sci. 2015;64(4):347-56. doi: 10.5650/jos.ess14281
  45. ↑ J Oleo Sci. 2015;64(4):347-56. doi: 10.5650/jos.ess14281
  46. ↑ Diabetol Metab Syndr. 2014 Feb 24;6(1):25. doi:10.1186/1758-5996-6-25
  47. ↑ Riahi Y; Cohen G; Shamni O; Sasson S. (2010). "Signaling and cytotoxic functions of 4-hydroxyalkenals". Am J Physiol Endocrinol Metab. 299 (6): E879–86. doi:10.1152/ajpendo.00508.2010. PMID 20858748.
  48. ↑ Kyung-Jin Cho; Ji-Min Seo; Jae-Hong Kim (2011). "Bioactive lipoxygenase metabolites stimulation of NADPH oxidases and reactive oxygen species". Molecules and Cells. 32 (1): 1–5. doi:10.1007/s10059-011-1021-7. PMC 3887656Freely accessible. PMID 21424583.
  49. ↑ Galano JM; Mas E; Barden A; Mori TA; Signorini C; De Felice C; Barrett A; Opere C; Pinot E; Schwedhelm E; Benndorf R; Roy J; Le Guennec JY; Oger C; Durand T. (2013). "Isoprostanes and neuroprostanes: Total synthesis, biological activity and biomarkers of oxidative stress in humans". Prostaglandins Other Lipid Mediat. 107: 95–102. doi:10.1016/j.prostaglandins.2013.04.003.
  50. ↑ Cohen G; Riahi Y; Sunda V; Deplano S; Chatgilialoglu C; Ferreri C; Kaiser N; Sasson S. (2013). "Signaling properties of 4-hydroxyalkenals formed by lipid peroxidation in diabetes". Free Radic Biol Med. 65: 978–87. doi:10.1016/j.freeradbiomed.2013.08.163. PMID 23973638.
  51. ↑ N Speed & I A Blair (2011). "Cyclooxygenase- and lipoxygenase-mediated DNA damage". Cancer Metastasis Rev. 30 (3-4): 437–47. doi:10.1007/s10555-011-9298-8. PMC 3237763Freely accessible. PMID 22009064.
  52. ↑ Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18820-4. doi:10.1073/pnas.0905415106
  53. ↑ PLoS One. 2013 Dec 9;8(12):e81228. doi: 10.1371/journal.pone.0081228. eCollection 2013
  54. ↑ J Clin Invest. 2010 May;120(5):1617-26. doi:10.1172/JCI41678
  55. ↑ J Clin Invest. 2010 May;120(5):1617-26. doi:10.1172/JCI41678
  56. ↑ Br J Pharmacol. 2013 Apr;168(8):1961-74. doi:10.1111/bph.12092
  57. ↑ J Neurosci. 2015 Jun 3;35(22):8593-603. doi:10.1523/JNEUROSCI.3993-14.2015
  58. ↑ J Biol Chem. 1992 Jul 15;267(20):14183-8
This article is issued from Wikipedia - version of the 5/17/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.