15-Hydroxyeicosatetraenoic acid (also termed15-HETE,15(S)-HETE, and15S-HETE) is aneicosanoid, i.e. a metabolite ofarachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initialhydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset ofspecialized pro-resolving mediators viz., thelipoxins, a class of pro-inflammatory mediators, theeoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.[1][2]
Some cell types (e.g.platelets) metabolize arachidonic acid to thestereoisomer of 15(S)-HpETE, 15(R)-HpETE. Both stereoisomers may also be formed as result of the metabolism of arachidonic acid by cellular microsomes or as a result of arachidonic acidauto-oxidation. Similar to 15(S)-HpETEs, 15(R)-HpETE may be rapidly reduced to 15(R)-HETE. TheseR,S stereoisomers differ only in having theirhydroxy residue in opposite orientations. While the twoR stereoisomers are sometimes referred to as 15-HpETE and 15-HETE, proper usage should identify them asR stereoisomers. 15(R)-HpETE and 15(R)-HETE lack some of the activity attributed to theirS stereoisomers but can be further metabolized to bioactive products viz., the 15(R) class oflipoxins (also termedepi-lipoxins).[3]
15(S)-HETE, 15(S)-HpETE, and many of their derivative metabolites are thought to have physiologically important functions. They appear to act ashormone-likeautocrine andparacrine signaling agents that are involved in regulatinginflammatory and perhaps other responses.[1][2][4] Clinically, drugs that are stable analogs, and therefore mimic the anti-inflammatory actions of the lipoxins and drugs that block the production or actions of the pro-inflammatory eoxins may prove useful for treating acute and chronicinflammatory disorders.[5]
15(S)-HETE is unambiguously designated by a shortened version of itsIUPAC name viz., 15(S)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid. In this terminologyS refers to theabsolute configuration of thechirality of the hydroxyfunctional group at carbon position 15. Its 15(R)enantiomer is designated 15(R)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid.Z andE give thecis–trans isomerism about eachdouble bond at carbon positions 5, 8, 11, and 13 with Z indicating cis and E indicating trans isomerism. Both stereoisomers are produced from their correspondingS andR 15-HpETE stereoisomers, i.e. 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HpETE) and 15(R)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(R)-HpETE).
Human cells releasearachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) from its storage site inphospholipids by reactions that involvephospholipase C and/orlipase enzymes. This release is stimulated or enhanced by cell stimulation. The freed arachidonic acid is then converted to 15-hydroperoxy/hydroxy products by one or more of the following five pathways.
15-Lipoxygenase-1: Cells metabolize arachidonic acid with 15-lipoxygenase-1 (i.e., 15-LO-1,ALOX15) to form 15(S)-HpETE as a major product and 12(S)-hydroperoxy-5Z,8Z,10E,15Z-eicosatetraenoic acid (12(S)-HpETE) and 14(S),15(S)-trans-oxido-5Z,8Z,11Z-14,15-leukotriene A4 as minor products; 15(S)-HpETE and 12(S)-HpETE are rapidly converted to 15(S)-HETE and 12(S)-hydroxy-5Z,8Z,10E,15Z-eicosatetraenoic acid (12(S)-hydroxyeicosatetraenoic acid), (i.e. 12(S)-HETE), respectively, or further metabolized through other enzyme pathways; 14(S),15(S)-trans-oxido-5Z,8Z,11Z-14,15-leukotriene A4 is metabolized by 15-LO-1 to various isomers of 8,15(S)-dihydroxy-5S,8S,11Z,13S-eicosatetraenoic acids, e.g. 8,15(S)-LTB4's.[6][7][8][9][10]
15-Lipoxygenase-2: Cells also used 15-lipoxygenase 2 (i.e. 15-LOX-2 orALOX15B) to make 15(S)-HpETE and 15(S)-HETE. However this enzyme has a preference for metabolizinglinoleic acid rather than arachidonic acid. It therefore forms linoleic acid metabolites (e.g.13-hydoxyperoxy/hydroxy-octadecadienoic and9-hydroperoxy/hydroxyl-octadecadienoic acids) in greater amounts than 15(S)-HpETE and 15(S)-HETE. 15-LOX-2 also differs from 15-LOX-1 in that it does not make 12(S)-HpETE or the leukotriene A4 isomer cited above.[10]
Cyclooxygenase: Cells can useprostaglandin-endoperoxide synthase 1 (i.e. cyclooxygenenase-1 or COX-1) andprostaglandin-endoperoxide synthase 2 (COX-2) to metabolize arachidonic acid primarily toprostaglandins but also to small amounts of 11(R)-HETE and a racemic mixture of 15-HETEs composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE.[11] When pretreated withaspirin, however, COX-1 is inactive while COX-2 attacks arachidonic acid to produce almost exclusively 15(R)-HETE along with its presumed precursor 15(R)-HpETE.[11][12][13]
Microsome metabolism: Human and rat microsomalcytochrome P450s, e.g. CYP2C19, metabolize arachidonic acid to aracemic mixture of 15-HETEs, i.e., 15(R,S)-HETEs, >90% of which is the 15(R) stereoisomer.[14][15]
Autoxidation: The spontaneous and non-enzymatically inducedautoxidation of arachidonic acid yields 15(R,S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acids. This non-enzymatic reaction is promoted in cells undergoingoxidative stress. Cells forming thisracemic mixture of 15-hydroperoxy products may convert then to 15(R,S)-HETEs and other products. However, the uncontrolled overproduction of the 15-hydroperoxy products may react with other elements to produce cell injury.[16][17]
The newly formed products formed by the pathways cited in the previous section are bioactive but may also flow into down-stream pathways to form other metabolites with a different sets of bioactivity. The initially formed 15(S)-HpETE may be further metabolized by its parent cell or pass it to nearby cell by a process termedtranscellular metabolism.
Metabolized by 15-LO-1 to its 14,15-trans-epoxide, 14,15-trans-epoxide-oxido-5Z,8Z,10E,13E-eicosatetraenoic acid (i.e.,eoxin A4 or EXA4), and thereafter to 14(R)-glutothionyl-15(S)-hydroxy-5Z,8Z,10E,13E-eicosatetraenoic acid (i.e. eoxin C4 or EXC4) byleukotriene C4 synthase.[26][27][28] EXC4 containsglutathione (i.e. γ-L-glutamyl-L-cysteinylglycine) bound in theR configuration to carbon 14. EXC4 is further metabolized by removal of the γ-L-glutamyl residue to form EXD4 which is in turn further metabolized by removal of the glycine residue to form EXE4.[26] These metabolic transformations are similar to those in the pathway that metabolizes arachidonic acid toLTA4,LTC4,LTD4, andLTE4 and presumed to be conducted by the same enzymes[26][28][27] (Eoxins are also termed 14,15-leukotrienes or 14,15-LTs).
Metabolized alternatively by 15-LO-1 to various 8,15-diHETEs including the two 8(R) and 8(S)diastereomers of 8,15(S)-dihydroxy-5,9,11,13-eicosatetraenoic acid (8,15-leukotrienes B4) and to two isomericerythro-14,15-dihydroxy-5-cis-8,10,12-eicosatetraenoic acids (14,15-leukotrienes B4).[29][30][31]
Metabolized by 15-LOX-2 to 11(S)-hydroxy-14(S),15(S)-epoxy-5(Z),8(Z),12(E)-eicosatrienoic acid and 13(R)-hydroxy-14(S),15(S)-epoxy-5(Z),8(Z),11(Z)-eicosatrienoic acid; these two products are novelhepoxilins produced by ALOX15 rather than ALOX12, the enzyme responsible for making the various other hepoxilins in humans.[32] The two novel hepoxilins are termed respectively14,15-HXA3 and14,15-HXB3. 14,15-HXA3 can be further metabolized by glutathione transferases to 11(S),15(S)-dihydroxy-14(R)-glutathionyl-(5Z),8(Z),12(E)-eicosatrienoic acid (14,15-HXA3C) which is then further metabolized to 11(S),15(S)-dihydroxy-14(R)-cysteinyl-glycyl-(5Z),8(Z),12(E)-eicosatrienoic acid (14,15-HXA3D).[32]
Isomerized to 15(S)-hydroxy-11,12-cis-epoxy-5Z,8Z,13E-eicosatrienoic acid (i.e., 15-H-11,12-EETA) by a hydroperoxide isomerase activity and then to 11,12,15-trihydroxy-5Z,8Z,12E-eicosatrienoic acid (i.e. 11,12,15-THETA) and 11,14,15-trihydroxy-5Z,8Z,12E-eicosatrienoic acid (i.e., 11,14,15-THETA) by a soluble epoxide hydrolase activity or, by acid in a non-enzymatic reaction (the R, S configuration of the hydroxy residues in the latter two metabolites has not been defined).[33]
Isomerized tothreo anderythro diastereoisomers of 13-hydroxy-14,15-cis-epoxy-5Z,8Z,11Z-eicosatrienoic acid (i.e., 15-H-11,12-EETA) by a hydroperoxide isomerase activity, possibly acytochrome P450, i.e. CYP2J2.[34]
Metabolized in skinepidermis by epidermis-type lipoxygenase 3 (eLOX3, encoded by theALOXE3 gene) to make two products,hepoxilin A3 (HxA3, i.e., 13R-hydroxy-14(S),15(S)-epoxy-5Z,8Z,11Z-eicosatetraenoic acid) and 15-oxo-ETE).[36]
Converted to its 14,15-epoxide derivative, eoxin A4, and further metabolized to eoxin C4, eoxin D4, and eoxin E4 (there is no eoxin B4).[37]
Oxidized to itsketo analog, 15-oxo-ETE, by the same enzyme that convertsprostaglandins of the A, E, and F series to their 15-keto analogs viz., NAD+-dependent15-hydroxyprostaglandin dehydrogenase; 15-oxo-ETE, similar to 15(S)-HETE, may be acylated into membrane phosphatidylethanolamine[23][24] or, similar to 15(S)-HpETE, conjugated withglutathione to form a 13-cysteinyl-glycyl-glutamine adduct viz., 13-glutatione,15-oxo-5(S),8(Z),11(E)-eicosatrienoic acid; the latter metabolite is attacked by γ-glutamyl-transferase to form 13-cysteinyl-glycine,15-oxo-5(S),8(Z),11(E)-eicosatrienoic acid.[39]
Acylated into membranephospholipids, particularlyphosphatidylinositol andphosphatidylethanolamine. Phospholipid products contain this 15(S)-HETE most likely at thesn-2 position. 15(S)-HETE-containing-phospholipids may also be made directly by the action of 15-LO-1 on membrane phosphatidylinositols or phosphatidylethanolamines containing arachidonic acid at thesn-2 positions.[21][40][41][42] The phosphatidylethanolamine-bound 15-HETE may be converted to phosphatidylethanolamine-bound 15-oxo-ETE.[24]
Oxygenated by 5-lipoxygenase (ALOX5) to form its 5,6-trans epoxide derivative which may then rearrange to thelipoxins (LX), LXA4 (i.e. 5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid) and LXB4 (i.e., 5(S),14(R),15(S)-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid)[3] or to 5(S),15(S)-dihydroperoxy-6E,8Z,11Z,13E-eicosatetraenoate (i.e., 5(S),15(S)-diHETE).[43][44] 5(S),15(S)-diHETE may then be oxidized to 5-oxo-15(S)-hydroxy-6E,8Z,11Z,13E-eicosatetraenoate (i.e., 5-oxo-15(S)-hydroxy-ETE). The latter two metabolites may also be made by 15-LO's metabolism of5-hydroxyeicosatetraenoic acid (i.e. 5-HETE) and5-oxo-eicosatetraenoic acid (i.e. 5-oxo-ETE), respectively.[45][46]
15(R)-HpETE may be:
Reduced to 15(R)-HETE by the same pathway that reduces 5(S)-HpETE to 15(S)-HETE.[38]
Similar to 15(S)-HpETE, subject to decomposition to form various bifuctional potentially toxic electrophiles such as 4-hydroxy-2(E)-nonenal and 4-oxo-2(E)-nonenal.[38]
15(R)-HETE may be:
Similar to 15(S)-HETE, oxidized by NAD-dependent 5-hydroxyprostaglandin dehydrogenase to form 15-oxo-ETE which product can be converted its 13-cysteinyl-glycyl-glutamyl and then 13-cysteinyl-glycine products as described above for 5(S)-HETE.[39]
Similar to 15(S)-HETE, oxygenated by ALOX5 to form its 5,6-oxido derivative which then rearranges to the 15(R)diastereomers of LXA4 and (LXB4 viz., 15-epi-LXA4 5(S),6(R),15(R)-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid) and 15-epi-LXB4 (i.e., 5(S),14(R),15(S)-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid, respectively.[43][3]
Most studies have analyzed the action of 15(S)-HETE but not that of its less stable precursor 15(S)-HpETE. Since this precursor is rapidly converted to 15(S)-HETE in cells, it is likely that the two metabolites share similar activities. In many studies, however, is not clear that these activities reflect their intrinsic action or reflect their conversion to the metabolites sited above.
15(S)-HpETE and 15(S)-HETE bind to and activate theG protein-coupled receptor,leukotriene B4 receptor 2, i.e. BLT2.[47] This receptor activation may mediate, at least in part, certain cell-stimulating activities of the two metabolites. BLT2 may be responsible in part or whole for mediating the growth-promoting and anti-apoptosis (i.e. anti-cell death) activities of 15(S)-HETE in cultured human breast cancer cells;[48] human cancer colon cells,[49] human hepatocellular HepG2 and SMMC7721 cancer cells;[50] mouse3T3 cells (afibroblast cell line);[51] rat PA adventitia fibroblasts;[52]baby hamster kidney cells;[53] and diverse types of vascularendothelial cells.[54][55][56][57] These growth-stimulating effects could contribute to the progression of the cited cancer types in animal models or even humans[48][49] and the excessfibrosis that causes the narrowing of pulmonary arteries in hypoxia-inducedpulmonary hypertension[51] or narrowing of portal arteries in theportal hypertension accompanying liver cirrhosis.[58] 15(S)-HETE may also act through BLT2 to stimulate an immediate contractile response in rat pulmonary arteries[59] and itsangiogenic effect on human umbilical[55] and dermal[54] vascular endothelial cells.
15(S)-HpETE and 15(S)-HETE also directly bind with and activateperoxisome proliferator-activated receptor gamma.[60] This activation may contribute to the ability of 15(S)-HETE to inhibit the growth of cultured human prostate cancerPC-3,LNCaP, andDU145 cell lines and non-malignant human prostate cells;[61][62] lung adenocarcinomaA549 cells;[63] human colorectal cancer cells;[64] corneal epithelial cells;[65] andJurkat T-cell leukemia cells.[66] The decline in the level of 15(S)-HpETE-forming enzymes and consequential fall in cellular 15-HETE production that occurs in human prostate cancer cells may be one mechanism by which this and perhaps other human cancer cells (e.g. those of the colon, rectum, and lung) avoid the apoptosis-inducing actions of 15(S)-HpETE and/or 15(S)-HETE and thereby proliferate and spread.[67][68] In this scenario, 15(S)-HETE and one of its forming enzymes, particularly 15-LOX-2, appear to act as tumor suppressors.
Some of the inhibitory effects of 15(S)-HpETE and 15(S)-HETE, particularly when induced by high concentrations (e.g. >1-10 micromolar), may be due to a less specific mechanism: 15(S)-HpETE and to a lesser extent 15(S)-HETE induce the generation ofreactive oxygen species. These species trigger cells to activate their death programs, i.e.apoptosis, and/or are openly toxic to the cells.[69][70][66][71][72] 15(S)-HpETE and 15(S)-HETE inhibit angiogenesis and the growth of cultured human chronic myelogenous leukemia K-562 cells by a mechanism that is associated with the production of reactive oxygen species.[55][73][74]
Several bifunctional electrophilic breakdown products of 15(S)-HpETE, e.g. 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, andcis-4,5-epoxy-2(E)-decanal, aremutagens in mammalian cells and thereby may contripute to the development and/or progression of human cancers.[38]
Similar to 15(S)-HpETE and 15(S)-HETE and with similar potency, 15(R)-HETE binds with and activates peroxisome proliferator-activated receptor gamma.[60] The precursor of 15(R)-HETE, 15(R)-HpETE may, similar to 15(S)-HpETE, break down to the mutagenic products 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, andcis-4,5-epoxy-2(E)-decanal and therefore be involved in cancer development and/or progression.[38]
In cultured human monocytes of theTHP1 cell line, 15-oxo-ETE inactivates IKKβ (also known asIKK2) thereby blocking this cell'sNF-κB-mediated pro-inflammatory responses (e.g.lipopolysaccharide-induced production ofTNFα,interleukin 6, andIL1B) while concurrently activating anti-oxidant responses upregulated through the anti-oxidant response element (ARE) by forcing cytosolicKEAP1 to releaseNFE2L2 which then moves to the nucleus, binds ARE, and induces production of, e.g. hemoxygenase-1, NADPH-quinone oxidoreductase, and possibly glutamate-cysteine ligase modifier.[75] By these actions, 15-oxo-ETE may dampen inflammatory and/oroxidative stress responses. In a cell-free system, 15-oxo-ETE is a moderately potent (IC50=1 μM) inhibitor of12-lipoxygenase but not other human lipoxygenases.[76] This effect could also have anti-inflammatory and anti-oxidative effects by blocking the formation of12-HETE andhepoxilins. 15-Oxo-ETE is an example of an α,β unsaturated ketoneelectrophile. These ketones are highly reactive withnucleophiles, adducting to, for example, the cysteines in transcription and transcription-related regulatory factors and enzymes to form their alkylated and thereby often inactivated products.[76][77] It is presumed that the preceding activities of 15-oxo-ETE reflect its adduction to the indicated elements.[75] 15-Oxo-ETE, at 2-10 μM, also inhibits the proliferation of culturedhuman umbilical vein endothelial cells andLoVo humancolorectal cancer cells[78][79] and at the extremely high concentration of 100 μM inhibits the proliferation of cultured MBA-MD-231 and MCF7 breast cancer cells as well as SKOV3 ovarian cancer cells.[80] They may use a similar "protein-adduction" mechanism; if so the target protein(s) for these effects have not been defined or even suggested. This 15-oxo-ETE action may prove to inhibit the remodeling of blood vessels and reduce the growth of the cited cell types and cancers. At sub-micromolar concentrations, 15-oxo-ETE has weakchemotaxis activity for humanmonocytes and could serve to recruit thiswhite blood cell intoinflammatory responses.[81]
LXA4, LXB4, AT-LXA4, and AT-LXB4 arespecialized proresolving mediators, i.e. they potently inhibit the progression and contribute to the resolution of diverse inflammatory and allergic reactions.
Eoxin A4,eoxin C4,eoxin D4, andeoxin E4 are analogs ofleukotriene A4,C4,leukotriene D4, andE4. Formation of the leukotrienes is initiated by 5-lipoxygenase metabolism of arachidonic acid to form a 5,6-epoxide viz, leukotriene A4; the latter metabolite is then converted to C4, D4, and E4 in succession. Formation of the eoxins is initiated by a 15-lipoxyenase-mediated metabolism of arachiconic acid to a 14,15-epoxide, eoxin A4 followed by its serial conversion to epoxins C4, D4, and E4 using the same pathways and enzymes that metabolize leukotriene A4 to its down-stream products. Preliminary studies have found that the eoxins have pro-inflammatory actions, suggest that they are involved in severe asthma, aspirin-induced asthma attacks, and perhaps other allergic reactions. The production of eoxins by Reed-Sternburg cells has also led to suggestion that they are involve in the lymphoma of Hodgkins disease.[27] Drugs blocking the 15-lipoxygenases may be useful for inhibiting inflammation by reducing the production of the eoxins.[83]
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