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 stereoisomer, 13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE). The adjacent figure gives the structure for the (S) stereoisomer of 13-HODE. Two other naturally occurring 13-HODEs that may accompany the production of 13(S)-HODE are 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 (ALOX15), while best known for converting the 20 carbon polyunsaturated fatty acid, arachidonic acid, into a series of 15-hydroxylated arachidonic acid metabolites (see 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). 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) -. In cells, 13(S)-HpODE is rapidly reduced by peroxidases to 13(S)-HODE. ALOX15 is fully capable of metabolizing the linoleic acid that is bound to phospholipid or cholesterol 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; nonetheless, it can contribute to the production of these metabolites.
Cyclooxygenases 1 and 2
Cyclooxygenase 1 (COX-1) and 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; consequently, COX-2 appears to be the principle COX making 13(S)-HODE in cells expressing both enzymes. Concurrently with their production of 13(S)-HODE, these enzymes also produce smaller amounts of 9(R)-HODE.
Cytochrome P450
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.