Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:54845-95-3 (15(S)-HETE)
 131 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolites of arachidonic acid have been implicated in the regulation of aldosterone release. To form a basis for further investigations in this area, the present study has isolated and identified the metabolites formed from exogenous arachidonic acid by adrenal zona glomerulosa cells and characterized the effects of several inhibitors on the synthesis of these eicosanoids. Rat adrenal glomerulosa cells metabolized exogenous [14C]arachidonic acid to products comigrating with the prostaglandins (PGs), hydroxyeicosatatraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs). The metabolites were found in the cells and the incubation media; however, none of the metabolites were found esterified to cellular lipids. The major metabolites were identified as 6-keto PGF1 alpha, PGE2, PGF2 alpha, PGD2, 12(S)-HETE, 15(S)-HETE, 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET. The identities of the HETEs and EETs were confirmed by gas chromatography/mass spectrometry. There was no evidence for the synthesis of leukotrienes. The cyclooxygenase inhibitor, indomethacin, the lipoxygenase inhibitors, nordihydroguaiaretic acid, baicalein and AA861, and the combined cyclooxygenase/lipoxygenase inhibitors, BW755C and eicosatetrayenoic acid, inhibited the formation of the [14C]PGs, the [14C]HETEs, and the [14C]EETs. Metyrapone and clotrimazole, inhibitors of cytochrome P450, increased the synthesis of [14C]PGs and [14C]HETEs and reduced the synthesis of [14C] EETs. Superoxide dismutase did not alter arachidonic acid metabolism. In contrast, arachidonic acid metabolism was increased in cells pretreated with catalase. These data indicate that adrenal glomerulosa cells metabolize exogenous arachidonic acid to a number of oxygenated metabolites including PGs, HETEs, and EETs. From studies with inhibitors, the EETs appear to be synthesized by a cytochrome P450 epoxygenase and the HETEs by lipoxygenases.
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PMID:Metabolism of arachidonic acid by rat adrenal glomerulosa cells: synthesis of hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. 190 Jul 88

The pure lipoxygenases from rabbit reticulocytes and soybeans convert a variety of substrates (arachidonic acid, 15-HPETE, 15-HETE, 5-HETE, various DiHETE isomers) to trihydroxy eicosanoids containing a conjugated tetraene system (lipoxins). In general, the methyl esters are better substrates for lipoxin formation than are the free acids. Lipoxygenase inhibitors (5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid) strongly inhibit the lipoxin formation. The complete stereochemistry of the lipoxin B formed from 15S-HETE methyl ester has been established by co-chromatography with authentic standards on various types of HPLC columns, by GC/MS analysis, by gas liquid chromatography of the ozonolysis fragments of the menthoxy carbonyl derivatives and 1H-NMR studies. The molar absorption coefficient of the conjugated tetraenes was measured as epsilon 301 = 53,000. The lipoxins formed from 15-HETE and various DiHETE isomers are formed exclusively via the oxygenation pathway as shown by experiments under an 17O2 atmosphere and/or by anaerobic incubations. Our results indicate that lipoxins can be synthesized via lipoxygenase-catalyzed sequential oxygenation of polyenoic fatty acids and their hydro(pero)xy derivatives.
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PMID:Lipoxygenase catalyzed oxygenation of hydroxy fatty acids to lipoxins. 313 2

Products of the 15-lipoxygenase pathway of arachidonate metabolism, prepared by techniques that effectively free them from contaminants, were examined for their ability to influence human neutrophil degranulation. 15(S)-Hydroxyicosatetraenoate [15(S)-HETE], 8(S),15(S)-dihydroxyicosatetraenoate, and 5(S),15(S)-dihydroxyicosatetraenoate did not directly stimulate this response, but 5(S),15(S)-dihydroxyicosatetraenoate (158-5000 nM) enhanced degranulation responses elicited by platelet-activating factor and its structural analogues. It had no such effect on the degranulation responses elicited by a tripeptide chemotactic factor, phorbol myristate acetate, leukotriene B4, or ionophore A23187. In many of these respects, the potentiating actions of 5,15-dihydroxyicosatetraenoate paralleled the actions of 5(S)-hydroxyicosatetraenoate. Indeed, these two metabolites had potentiating actions on platelet-activating factor that were non-additive and, under specific conditions, cross-desensitized each other. Based on the structural specificity demonstrated by these and other mono- and dihydroxyeicosatetraenoates in potentiating platelet-activating factor as well as their mutual cross-desensitizing actions, we suggest that 5-hydroxylated arachidonate metabolites act by a structurally specific receptor to potentiate human neutrophil responses to certain stimuli.
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PMID:Effect of 15-lipoxygenase-derived arachidonate metabolites on human neutrophil degranulation. 392 Jun 80

The optimal conditions for the -in vitro- LTC4 formation by the human eosinophil, isolated from peripheral blood, have been investigated in detail. LTC4 formation was found strongly Ca2+ and ionophore dependent and was complete after 20 min. Maximal LTC4 production was observed in the presence of 2 mM Ca2+, 10 microM ionophore A23187 and 5 mM glutathione. Addition of arachidonic acid resulted in a significant inhibition of the LTC4-synthesis by human eosinophils. In contrast, the formation of 15-HETE was strongly stimulated by the addition of arachidonic acid. As the LTC4 synthesis was found to be strongly inhibited by the addition of 15(S)-HETE to the incubation medium, this monohydroxy acid may be responsible for the inhibitory activity of arachidonic acid.
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PMID:On the optimal conditions of LTC4 formation by human eosinophils in vitro. 393 83

Elicited rat peritoneal mononuclear cells converted arachidonic acid to a new dihydroxy acid, 5(S), 15(S)-dihydroxy-6,13-trans-8,11-cis-eicosatetraenoic acid (5,15-DiHETE). In this system, the amount of 5,15-DiHETE formed was about 20% that of leukotriene B4. The structure of the compound was determined by ultraviolet and mass spectrometric analysis, and comparison to a reference compound prepared by incubation of synthetic 5(R,S)-hydroxy- or hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5(R,S)-HETE or HPETE) with soybean lipoxygenase (linoleate:oxygen oxidoreductase, EC 1.13.11.12). Cell incubations performed under an atmosphere of 18O2 demonstrated that both hydroxyl groups in the cell product derived from molecular oxygen and that the oxygen atoms were from different oxygen molecules. Steric analysis indicated that each hydroxyl group had the S-configuration. The structural data thus indicate that 5,15-DiHETE is formed by an enzymatic double oxygenation of arachidonic acid catalyzed by both C-5 and C-15 lipoxygenases. Incubations with with [3H 8]5 (S)-HETE and [3H8]15(S)-HETE revealed that both compounds could be converted to the product. When [3H8]5(S), 15(S)-DiHPETE was added to cells, the majority of the substrate was reduced to 5,15-DiHETE. Leukocytes obtained from three human donors with peripheral blood eosinophilia also synthesized 5,15-DiHETE. Formation of the compound occurred in both eosinophils and neutrophils from these donors.
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PMID:Formation of a novel dihydroxy acid from arachidonic acid by lipoxygenase-catalyzed double oxygenation in rat mononuclear cells and human leukocytes. 680 63

Arachidonic acid metabolites have been implicated in the regulation of ACTH secretion. To define further which eicosanoid(s) is primarily involved, we examined the effects of both inhibitors of the three arachidonate metabolic pathways (cyclooxygenase, lipoxygenase, and epoxygenase) and specific eicosanoid products on ACTH secretion by rat pituitary corticotrophs in a microperifusion system. CRF stimulates sustained ACTH release that is mediated by protein kinase-A-induced extracellular Ca2+ (Cae2+) influx via L-type voltage-sensitive calcium channels (VSCC). Arginine vasopressin (AVP) stimulates an initial spike phase of ACTH release that presumably is mediated by inositol 1,4,5-trisphosphate-induced intracellular Ca2+ (Cai2+) release, followed by a sustained plateau phase of ACTH release that is mediated by protein kinase-C-induced Cae2+ influx via L-type VSCC. Pretreatment for 15 min with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 50 microM), but not the cyclooxygenase inhibitor indomethacin (10 microM) or the epoxygenase inhibitor SKF525A (100 microM) inhibited the sustained response to CRF by 48% and the initial spike response to AVP by 38%. NDGA-induced inhibition was not reversed by indomethacin or SKF525A, alone or in combination, precluding arachidonate shunting into other pathways. However, the results suggested that epoxygenase metabolites may have a minor stimulatory and cyclooxygenase metabolites may have a minor inhibitory effect on ACTH secretion. Preexposure to NDGA suppressed by 43% the sustained response to 8-bromo-cAMP, which directly activates protein kinase-A; by 57% the sustained response to dioctanolglycerol, which directly activates protein kinase-C; and by 59% the spike-type response to ionomycin, which releases Cai2+ by an inositol 1,4,5-trisphosphate-independent mechanism. These results suggest that NDGA either inhibits the production of a lipoxygenase metabolite involved in Cae2+ influx and/or Cai2+ release or acts other than by inhibiting lipoxygenase, such as by directly blocking membrane transport of Cae2+. The three major lipoxygenase metabolites tested, 5(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acid (HETE), all stimulated sustained ACTH release in a dose-dependent manner. At a concentration of 2 microM, 12(S)-HETE was 4.7 and 2.5 times more potent than 5(S)- and 15(S)-HETE, respectively, and completely reversed NDGA inhibition of both CRF- and AVP-stimulated ACTH secretion. The ACTH-releasing activity of 12(S)-HETE was inhibited 26% by removing Cae2+ and 54% by both removing Cae2+ and depleting Cai2+, indicating either that 12(S)-HETE facilitates transmembrane Ca2+ transfer or that increased cytosolic Ca2+ is necessary for 12(S)-HETE's action.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of lipoxygenase metabolites of arachidonic acid in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells. 752

15-Hydroxyeicosatetraenoic acid [15-(S)-HETE], a major arachidonic acid metabolite produced from the 15-lipoxygenase pathway, has been characterized as an antiinflammatory cellular mediator since it can inhibit the in vivo and in vitro formation of the proinflammatory leukotrienes via the 5-lipoxygenase pathway in various cells. 15-HETE has been confirmed to inhibit the 5-lipoxygenase in rat basophilic leukemia cell (RBL-1) homogenates with an I50 = 7.7 microM. The I50 of the 12-HETE isomer was 6 microM whereas prostaglandin F2 alpha was ineffective. In order to examine the mechanistic basis underlying the inhibitory action of 15-HETE, association assays of [3H]-15-HETE with RBL-1 subcellular fractions were carried out. The presence of the zwitterionic detergent CHAPS enhanced specific [3H]-15-HETE binding in the membrane fractions three-fold and specific 15-HETE binding was distributed among the nuclear (32%)-, granule (19%)-, plasma membrane (35%)-, and cytosol (14%)-enriched fractions. Studies using combined granule and plasma membrane enriched-, CHAPS treated-fractions showed that [3H]-15-HETE binding was time-dependent, specific and reversible, sensitive to pertussis toxin treatment, and indicated a single class of binding sites with a Kd = 460 +/- 160 nM and Bmax = 5.0 +/- 1.1 nM. Competition experiments showed that the order of 15-HETE or analogs in inhibiting the binding of [3H]-15-HETE was: 15(S)-HETE > or = 12-(S)-HETE = 5-(S)-HETE > 15-(R)-HETE > arachidonic acid. Prostaglandin F2 alpha and lipoxin B4 were ineffective as competitors. The similar profiles of the binding assays and inhibition of the 5-lipoxygenase suggest that 15-HETE binding sites may mediate this inhibitory action of 15-HETE.
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PMID:Characterization of specific subcellular 15-hydroxyeicosatetraenoic acid (15-HETE) binding sites on rat basophilic leukemia cells. 778 91

The extent of epidermal fatty acid oxygenase activation in non-psoriatic dermatoses and the nature of these oxygenases are not known. The monohydroxylated fatty acid derivatives produced in vivo and trapped in skin scales or produced in vitro by oxygenases preserved in scales were analyzed by high performance liquid chromatography in 10 patients with non-psoriatic dermatoses. Evidence for 15-lipoxygenase activation included the finding of 15(S)-hydroxyeicosatetraenoic acid (HETE) in scales from seven patients and the production of 15(S)-[14C]HETE and 13(S)-[14C]hydroxyoctadecadienoic acid (HODE) during scale incubations, respectively, with [14C]arachidonic and [14C]linoleic acid. Evidence for the activation of an arachidonic acid 12(R)-oxygenase included the finding of 12(R)-HETE in scales from eight patients and the production of 12(R)-[14C]HETE during scale incubations with [14C]arachidonic acid. 13-HODE was the predominant fatty acid derivative present in scale extracts; its lack of enantiopurity (mean S/R = 3.1) and the substantial formation of 9-HODE (mean S/R = 0.6; 9/13-HODE = 0.43) suggest its derivation from 15-lipoxygenase and a second oxygenase. The levels of 15(S)-HETE and 12(R)-HETE had a 125- to 144-fold range and were highest in scales from a patient with erythroderma and in three psoriatic scale samples similarly analyzed. These findings indicate that 15-lipoxygenase, most likely of keratinocyte origin, and an arachidonic acid 12(R)oxygenase of unknown type and cell origin are activated in diverse dermatoses.
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PMID:Epidermal fatty acid oxygenases are activated in non-psoriatic dermatoses. 782 82

Neonatal rat lens epithelium has a high 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] synthetic capacity, which decreases as epithelial cell proliferation decreases with age. To determine whether products of the 12-lipoxygenase pathway are involved in lens cell proliferation, we measured the effect of 12-lipoxygenase inhibitors on endogenous 12-HETE production, epidermal growth factor/insulin-stimulated DNA synthesis and protooncogene expression in cultured neonatal rat lens epithelial cells. Incubation of neonatal rat lenses in epidermal growth factor plus insulin, which stimulated endogenous 12-HETE production 8- to 10-fold, also produced a transient induction of c-fos and c-myc mRNAs after 2 to 3 h, followed by a round of DNA synthesis approximately 20 h later. The lipoxygenase inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, strongly inhibited both the endogenous 12-HETE synthesis and growth factor-stimulated DNA synthesis with a half-maximal inhibition between 10 and 20 microM. Cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (10 microM) also inhibited the expression of c-fos and c-myc mRNA and, to a lesser extent, c-jun mRNA. The inhibitory effects of cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate on protooncogene expression and DNA synthesis were prevented by 0.3 microM 12(S)-HETE but not by equivalent concentrations of either 5(S)-HETE or 15(S)-HETE. These findings suggest that endogenously synthesized 12(S)-HETE may mediate epidermal growth factor/insulin-stimulated DNA synthesis in neonatal rat lens epithelial cells by regulating protooncogene expression.
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PMID:12(S)-hydroxyeicosatetraenoic acid regulates DNA synthesis and protooncogene expression induced by epidermal growth factor and insulin in rat lens epithelium. 784 8

5-Lipoxygenase products, such as leukotrienes, are important stimuli for leukocyte-mediated tissue injury in acute inflammation. 15-Hydroxyeicosatetraenoic acid (15-HETE) is an eicosanoid generated by a variety of cell types via the actions of 15-lipoxygenases and, in addition, cyclooxygenases and epoxygenases. 15-HETE levels are frequently elevated at sites of inflammation, and extracellular 15(S)-HETE is esterified rapidly into neutrophil (PMN) phospholipids in vitro to levels that are comparable with arachidonic acid. We present evidence that remodeling of PMN phospholipids with 15(S)-HETE stereoselectively inhibits PMN migration across endothelium in response to leukotriene B4 (LTB4) and other chemoattractants. Esterified 15(S)-HETE causes a striking reduction in the affinity of LTB4 cell-surface receptors for their ligand and inhibition of LTB4-triggered stimulus-response coupling. As a result of these actions, esterified 15(S)-HETE attenuates the cytoskeletal rearrangements and CD11/CD18-mediated adhesive events that subserve directed locomotion of PMN across endothelium. These observations indicate that products of the 5-lipoxygenase and 15-lipoxygenase pathways can exert counterbalancing influences on PMN trafficking across endothelium. They suggest that 15(S)-HETE may be a potent endogenous inhibitor of PMN-endothelial interactions in vivo and serve to limit or reverse acute inflammation.
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PMID:Remodeling of neutrophil phospholipids with 15(S)-hydroxyeicosatetraenoic acid inhibits leukotriene B4-induced neutrophil migration across endothelium. 790 93


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