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9-Hydroxyoctadecadienoic acid
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9-Hydroxyoctadecadienoic acid
9-Hydroxyoctadecadienoic 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.
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. 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. 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.
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. 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%.
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. 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). 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. 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.
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. However, ALOX15B, similar to human 15-lipoxygenase-1 (ALOX15), metabolizes linoleic acid to 13(S)-HODE but not to 9(S)-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); since, however, the linoleic acid bound to cellular phospholipids is susceptible to non-enzymatic peroxidation and free-radical attack, 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 cytosol (see phospholipase A2 section on cPLA2) and therefore may serve as a storage pool that is mobilized by cell stimulation.
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.
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9-Hydroxyoctadecadienoic acid
9-Hydroxyoctadecadienoic 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.
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. 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. 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.
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. 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%.
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. 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). 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. 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.
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. However, ALOX15B, similar to human 15-lipoxygenase-1 (ALOX15), metabolizes linoleic acid to 13(S)-HODE but not to 9(S)-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); since, however, the linoleic acid bound to cellular phospholipids is susceptible to non-enzymatic peroxidation and free-radical attack, 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 cytosol (see phospholipase A2 section on cPLA2) and therefore may serve as a storage pool that is mobilized by cell stimulation.
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.
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