5-Hydroxyeicosatetraenoic acid


5-Hydroxyeicosatetraenoic acid is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5-HETE to 5-oxo-eicosatetraenoic acid, 5,15-dihydroxyeicosatetraenoic acid,15, or 5-oxo-15-hydroxyeicosatetraenoic acid.
5-HETE, 5-oxo-ETE, 5,15-diHETE, and 5-oxo-15-HETE, while differing in potencies, share a common mechanism for activating cells and a common set of activities. They are therefore a family of structurally related metabolites. Animal studies and a limited set of human studies suggest that this family of metabolites serve as hormone-like autocrine and paracrine signalling agents that contribute to the up-regulation of acute inflammatory and allergic responses. In this capacity, these metabolites may be members of the innate immune system.
In vitro studies suggest that 5-HETE and/or other of its family members may also be active in promoting the growth of certain types of cancers, in simulating bone reabsorption, in signaling for the secretion of aldosterone and progesterone, in triggering parturition, and in contributing to other responses in animals and humans. However, the roles of 5-HETE family members in these responses as well as in inflammation and allergy are unproven and will require much further study.
Among the 5-HETE family members, 5-HETE takes precedence over the other members of this family because it was the first to be discovered and has been studied far more thoroughly. However, 5-oxo-ETE is the most potent member of this family and therefore may be its critical member with respect to physiology and pathology. 5-OxoETE has gained attention in recent studies.

Nomenclature

5-Hydroxyeicosatetraenoic acid is more properly termed 5-hydroxyicosatetraenoic acid or 5 to signify the configuration of its 5-hydroxy residue as opposed to its 5-hydroxyicosatetraenoic acid stereoisomer. Since 5-HETE was rarely considered in the early literature, 5-HETE was frequently termed 5-HETE. This practice occasionally continues. 5-HETE's IUPAC name, -5-hydroxyicosa-6,8,11,14-tetraenoic acid, defines 5-HETE's structure unambiguously by notating not only its S-hydroxyl chirality but also the cis–trans isomerism geometry for each of its 4 double bonds; E signifies trans and Z signifies cis double bond geometry. The literature commonly uses an alternate but still unambiguous name for 5-HETE viz., 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid.

History of discovery

The Nobel laureate, Bengt I. Samuelsson, and colleagues first described 5-HETE in 1976 as a metabolite of arachidonic acid made by rabbit neutrophils. Biological activity was linked to it several years later when it was found to stimulate human neutrophil rises in cytosolic calcium, chemotaxis, and increases in their cell surface adhesiveness as indicated by their aggregation to each other. Since a previously discovered arachidonic acid metabolite made by neutrophils, leukotriene B4, also stimulates human neutrophil calcium rises, chemotaxis, and auto-aggregation and is structurally similar to 5-HETE in being a 5-hydroxy-eicosateraenoate, it was assumed that 5-HETE stimulated cells through the same cell surface receptors as those used by LTB4 viz., the leukotriene B4 receptors. However, further studies in neutrophils indicated that 5-HETE acts through a receptor distinct from that used by LTB4 as well as various other neutrophil stimuli. This 5-HETE receptor is termed the oxoeicosanoid receptor 1.

5(''S'')-HETE production

5-HETE is a product of the cellular metabolism of the n-6 polyunsaturated fatty acid, arachidonic acid, by ALOX5. ALOX5 metabolizes arachidonic acid to its hydroperoxide derivative, arachidonic acid 5-hydroperoxide i.e. 5-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid. 5-HpETE may then be released and rapidly converted to 5-HETE by ubiquitous cellular peroxidases:
Alternatively, 5-HpETE may be further metabolized to its epoxide, 5-oxido-eicosatetraenoic acid viz., leukotriene A4. Leukotriene A4 may then be further metabolized either to leukotriene B4 by leukotriene A4 hydrolase or to leukotriene C4 by leukotriene C4 synthase. Finally, leukotriene C4 may be metabolized to leukotriene D4 and then to leukotriene E4. The relative amounts of these metabolites made by specific cells and tissues depends in large part on the relative content of the appropriate enzymes.
The selective synthesis of 5-HETE -HETE without concurrent synthesis of 5 by cells is dependent on, and generally proportionate to, the presence and levels of its forming enzyme, ALOX5. Human ALOX5 is highly expressed in cells that regulate innate immunity responses, particularly those involved in inflammation and allergy. Examples of such cells include neutrophils, eosinophils, B lymphocytes, monocytes, macrophages, mast cells, dendritic cells, and the monocyte-derived foam cells of atherosclerosis tissues. ALOX5 is also expressed but usually at relatively low levels in many other cell types. The production of 5-HETE by these cells typically serves a physiological function. However, ALOX5 can become overexpressed at high levels in certain types of human cancer cells such as those of the prostate, lung, colon, colorectal and pancreatic as a consequence of their malignant transformation. In these cells, the ALOX5-dependent production of 5-HETE appears to serve a pathological function viz., it promotes the growth and spread of the cancer cells.
5-HETE may also be made in combination with 5-HETE along with numerous other -hydroxy polyunsaturated fatty acids as a consequence of the non-enzymatic oxidation reactions. Formation of these products can occur in any tissue subjected to oxidative stress.

5(''S'')-HETE metabolism

In addition to its intrinsic activity, 5-ETE can serve as an intermediate that is converted to other bioactive products. Most importantly, 5-Hydroxyeicosanoid dehydrogenase converts the 5-hydroxy residue of 5-HETE to a ketone residue to form 5-oxo-eicosatetraenoic acid. 5-HEDH is a reversibly acting NADP+/NADPH-dependent enzyme that catalyzes to following reaction:
5-HEDH acts bi-directionally: it preferentially oxygenates 5-HETE to 5-oxo-ETE in the presence of excess NADH+ but preferentially reduces 5-oxo-ETE back to 5-HETE in the presence of excess NADPH. Since cells typically maintain far higher levels of NADPH than NADP+, they usually make little or no 5-oxo-ETE. When undergoing oxidative stress, however, cells contain higher levels of NADH+ than NADPH and make 5-oxo-ETE preferentially. Additionally, in vitro studies indicate that cells can transfer their 5-HETE to cells that contain high levels of 5-NEDH and NADP+ and therefore convert the transferred 5-HETE to 5-oxo-ETE. It is suggested that 5-oxo-ETE forms preferentially in vivo under conditions of oxidative stress or conditions where ALOX5-rich cells can transfer their 5-HETE to cells epithelial, endothelial, dendritic, and certain cancer cells which display little or no ALOX5 activity but have high levels of 5-NEDH and NADP+. Since 5-oxo-ETE is 30- to 100-fold more potent than 5-HETE, 5-HEDH main function may be to increase the biological impact of 5-HETE production.
Cells metabolize 5--HETE in other ways. They may use:
  • An acyltransferase to esterify 5-HETE into their membrane phospholipids. This reaction may serve to storing 5-HETE for its release during subsequent cell stimulation and/or alter the properties of cell membranes in functionally important ways.
  • A cytochrome P450, probably CYP4F3, to metabolize 5-HETE to 5,20-dihydroxy-eicosatetraenoate. Since 5,20-diHETE is ~50- to 100-fold weaker than 5-HETE in stimulating cells, this metabolism is proposed to represent a pathway for 5-HETE inactivation.
  • ALOX15 to metabolize 5-HETE to 5,15-dihydroxy-eicosatetraenoate. 5,15-diHETE is ~3- to 10-fold weaker than 5-HETE in stimulating cells.
  • 12-Lipoxygenase to metabolize 5-HETE to 5,12-diHETE. The activity of this product has not yet been fully evaluated.
  • Cyclooxygenase-2 to metabolize 5-HETE to 5,15-diHETE and 5,11-diHETE. The activity of these products have not yet been fully evaluated.
  • Aspirin-treated cyclooxygenase-2 to metabolize 5-HETE to 5,15-diHETE. The activity of this product has not yet been fully evaluated.
Alternate pathways that make some of the above products include the: a) metabolism of 5-HpETE to 5-oxo-ETE by cytochrome P450 conversion of 5-HETE to 5-oxo-ETE non-enzymatically by heme or other dehydrating agents; c) formation of 5-oxo-15-hydroxy-ETE through 5-HEDH-based oxidation of 5,15 formation of 5,15 formation of 5-oxo-15 conversion of 5-HpETE and 5-HpETE to 5-oxo-ETE by the action of a mouse macrophage 50-60 kilodalton cytosolic protein.

Mechanism of action

The OXER1 receptor

5-HETE family members share a common receptor target for stimulating cells that differs from the receptors targeted by the other major products of ALOX5, i.e., leukotriene B4, leukotriene C4, leukotriene D4, leukotriene E4, lipoxin A4, and lipoxin B4. It and other members of the 5-HETE family stimulate cells primarily by binding and thereby activating a dedicated G protein-coupled receptor, the oxoeicosanoid receptor 1. OXER1 couples to the G protein complex composed of the Gi alpha subunit and G beta-gamma complex ; when bound to a 5--HETE family member, OXER1 triggers this G protein complex to dissociate into its Gαi and Gβγ components with Gβγ appearing to be the component responsible for activating the signal pathways which lead to cellular functional responses. The cell-activation pathways stimulated by OXER1 include those mobilizing calcium ions and activating MAPK/ERK, p38 mitogen-activated protein kinases, cytosolic phospholipase A2, PI3K/Akt, and protein kinase C beta and epsilon. The relative potencies of 5-oxo-ETE, 5-oxo-15-HETE, 5-HETE, 5,15-diHETE, 5-oxo-20-hydroxy-ETE, 5,20-diHETE, and 5,15-dioxo-ETE in binding to, activating, and thereby stimulating cell responses through the OXER1 receptor are ~100, 30, 5–10, 1–3, 1–3, 1, and <1, respectively.