Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.13.11.12 (lipoxygenase)
8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The R and S enantiomers of 12-hydroxyeicosatetraenoic acid (12-HETE) exhibit different biological activities. Although they appear to be produced by different enzymatic pathways, cytochrome P-450 monooxygenase and lipoxygenase, respectively, they display similar metabolism in both corneal epithelium and neutrophils. In corneal epithelial microsomes, both enantiomers are subject to oxidation and keto reduction reactions to form the dihydro metabolite, 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), via a keto intermediate. The apparent Km for the formation of 12-HETrE was 17.9 and 20 microM for 12(R)-HETE and 12(S)-HETE, respectively, and the apparent Vmax of the reaction was 17.4 and 8.2 pmol/mg per min, respectively. Chiral analysis of the dihydro metabolite demonstrated a product enantiospecificity. Arachidonic acid, 12(R)-HETE, 12(S)-HETE and the intermediate of this reaction, 12-oxo-ETrE, were metabolized predominantly to 12(R)-HETrE in a ratio [12(R)-HETrE: 12(S)-HETrE] of 7.3:1, 4.3:1, 1.5:1 and 2.3:1, respectively. 12(R)-HETrE is a potent vasodilator, chemotactic and angiogenic factor whose synthesis is induced in inflamed tissues; 12(S)HETrE is devoid of these properties. 12(R)-HETE, derived from NADPH-dependent cytochrome P-450 monooxygenases, and 12(S)-HETE, derived from 12-lipoxygenase, may both play an important role in regulating the inflammatory response by serving as substrates for the local synthesis of 12(R)-HETrE.
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PMID:Oxidation and keto reduction of 12-hydroxy-5,8,10,14-eicosatetraenoic acids in bovine corneal epithelial microsomes. 828 Jul 73

Human epidermal cells exhibited none of the cytosolic lipoxygenase activity that is prominent in mucosal epithelial cells, but instead contained a microsomal activity that converted arachidonic acid to 12-hydroxyeicosatetraenoic acid (12-HETE). Identification of the extractable 12-HETE-forming activity as a 12-lipoxygenase (distinct from cytochrome P-450) included (S)-12-stereospecificity of product formation, trapping of 12-hydroperoxyeicosatetraenoic acid as an intermediate reaction product, and lack of NADPH dependence for activity. Epidermal cell poly(A)+ RNA contained high levels of a 2.3-kb mRNA that selectively hybridized with human platelet 12-lipoxygenase cDNA, and partial cDNA sequence of this mRNA indicated identity to platelet 12-lipoxygenase. The epidermal 12-lipoxygenase was not recognized by antibodies against the leukocyte-type 12- and 15-lipoxygenases (found in leukocytes, reticulocytes, and mucosal epithelial cells) but was detected by an antiplatelet 12-lipoxygenase antibody. The epidermal 12-lipoxygenase antigen was selectively expressed in germinal layer keratinocytes in healthy and psoriatic skin, and these layers exhibited hyperplasia and increased immunostaining in inflamed psoriatic skin. Together with previous results, these observations indicate that 1) epidermis generates 12-HETE by either cytochrome P-450 or lipoxygenase-based mechanisms depending on reaction conditions, and 2) 12-lipoxygenases (originally described in hematopoietic cell types) may be expressed in at least two distinct isoforms in epithelial barriers in humans, and in the case of the skin, a microsomal (platelet-type) 12-lipoxygenase is selectively overexpressed in germinal layer keratinocytes during psoriatic inflammation.
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PMID:Epidermis contains platelet-type 12-lipoxygenase that is overexpressed in germinal layer keratinocytes in psoriasis. 830 20

Human skin fibroblasts labeled with [5,6,8,9,11,12,-14,15-3H]arachidonic acid produce a radioactive metabolite that has a shorter retention time on reverse-phase high-performance liquid chromatography than arachidonic acid. This product is not retained in the cells; it is released entirely into the extracellular fluid in a time-dependent manner. The metabolite does not cochromatograph with any of the eicosanoid standards, and its formation is not prevented by the addition of cyclooxygenase, lipoxygenase, or cytochrome P-450 inhibitors. The compound is not produced by fibroblasts labeled with [1-14C]arachidonic acid, suggesting that it is formed through an oxidative process. Chemical analyses indicated that the metabolite is 4,7,10-hexadecatrienoic acid (16:3). Peroxisome-deficient human skin fibroblasts did not produce 16:3, indicating that it probably is formed through peroxisomal beta-oxidation. Human umbilical vein endothelial cells and porcine pulmonary artery smooth muscle cells also release radioactive 16:3 following labeling with [3H]arachidonic acid. Therefore, the production of this metabolite is not limited only to fibroblasts. The fact that 16:3 is released into the extra-cellular fluid suggests that it may be a new type of lipid mediator derived from arachidonic acid, formed through a peroxisome-dependent oxidative process.
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PMID:Formation and release of a peroxisome-dependent arachidonic acid metabolite by human skin fibroblasts. 830 70

The role of arachidonic acid (AA) and its metabolites in vasopressin (AVP)-induced calcium mobilization in A7r5 aortic smooth muscle cells was explored by intracellular calcium monitoring, [14C]AA labeling, and high-performance liquid chromatography (HPLC) techniques. In fura 2-loaded A7r5 cells, AA potentiated AVP-stimulated increase in intracellular free Ca2+ ([Ca2+]i). The cyclooxygenase inhibitor indomethacin reduced both the AA- and AVP-induced influx of extracellular Ca2+. AVP-induced [Ca2+]i transients were not altered by lipoxygenase inhibitors but were reduced in a dose-dependent fashion by ketoconazole, an inhibitor of cytochrome P-450 monooxygenases. Among several epoxygenase metabolites of AA tested, 5,6-epoxyeicosatrienoic acid potentiated AVP-induced [Ca2+]i transients. Reverse-phase HPLC analysis of lipid extracts from A7r5 cells prelabeled with [14C]AA isolated a radioactive peak that did not coelute with established products of cyclooxygenase-, lipoxygenase-, or cytochrome P-450-catalyzed oxidations of AA. This peak was significantly increased after AVP stimulation and was completely blocked by preincubation with ketoconazole. Thus the stimulation of V1-vascular AVP receptors of A7r5 cells triggers several cytoplasmic signaling pathways involving AA metabolite formation through the cyclooxygenase and epoxygenase pathways.
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PMID:Role of eicosanoids in vasopressin-induced calcium mobilization in A7r5 vascular smooth muscle cells. 833 43

A homogenate of epidermal cells isolated from human skin converted arachidonic acid to 12S-hydroxy-5, 8,10,14-eicosatetraenoic acid and 15-hydroxy-5, 8,11,13-eicosatetraenoic acid as the main lipoxygenase products. The production of these hydroxy acids was not stimulated by the addition of 1 mM NADPH required for cytochrome P-450 reaction, but inhibited by 65-75% with 40 microM nordihydroguaiaretic acid, a nonspecific lipoxygenase inhibitor. In addition to these lipoxygenase products, the epidermal cell homogenate converted arachidonic acid to prostaglandin E2 together with minor amounts of prostaglandins D2 and F2a and 12-hydroxy-5,8,10-heptadecatrienoic acid. Thromboxane B2 was not detected. This finding rules out the possible contamination of platelet 12-lipoxygenase in the epidermal cells. After subcellular fractionation of the epidermal cell homogenate, the 12-lipoxygenase activity was found in the 164,000 x g supernatant, the 164,000 x g pellet, and the 10,000 x g pellet. The cytosolic enzyme and the enzymes solubilized from the two pellets produced 12S-hydroperoxy-5,8,10,14-eicosatetraenoic acid as the primary product in contrast to cytochrome P-450 which produces primarily hydroxy acids. The 12-lipoxygenase in the 164,000 x g supernatant and the solubilized enzymes from the 164,000 x g pellet and 10,000 x g pellet were precipitable by antibodies raised against human platelet 12-lipoxygenase, but not by antibodies against porcine leukocyte 12-lipoxygenase. The immunoprecipitated 12-lipoxygenase from each fraction was almost inactive with linoleic acid as substrate, characteristic of 12-lipoxygenase of platelet-type. Furthermore, 12-lipoxygenase mRNA in the epidermal cells could be reverse-transcribed and amplified by polymerase chain reaction with the primers specific for human platelet 12-lipoxygenase cDNA, but not with those for porcine leukocyte 12-lipoxygenase cDNA. Thus, the 12-lipoxygenase of human epidermal cells is similar to human platelet 12-lipoxygenase in terms of immunogenicity, catalytic property, and primary structure, and distinct from leukocyte 12-lipoxygenase.
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PMID:Arachidonate 12-lipoxygenase of platelet-type in human epidermal cells. 834 30

Because hypercholesterolemia and mesangial cell proliferation may be important in the pathogenesis of glomerulosclerosis, the effects of low-density lipoprotein (LDL) on human mesangial cell proliferation were evaluated. Native LDL (20 to 200 micrograms/mL) caused a dose-dependent increase in (3H)thymidine incorporation and increased mesangial cell numbers over 96 h. The mitogenic effect of LDL was partially blocked by the inhibition of cytochrome P-450, but not by the inhibition of cyclooxygenase or lipoxygenase pathways. Higher LDL concentrations (1,000 to 2,000 micrograms/mL) inhibited (3H)thymidine incorporation and reduced cell numbers, possibly as a result of the oxidative modification of LDL, indicated by an increase in thiobarbituric reactive substances. This peroxidation of LDL involved superoxide, because superoxide dismutase and butylated hydroxytoluene prevented it, whereas hydroxyl radical scavengers were without effect. Native LDL subjected to chemical oxidation by copper sulfate also inhibited mesangial cell proliferation. These results suggest that low concentrations of LDL may stimulate human mesangial cell proliferation, which may, in turn, cause the production of reactive oxygen molecules. Moreover, the oxidative modification of LDL may mediate the toxic effects of high LDL concentrations on human mesangial cells.
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PMID:Oxidative modification of low-density lipoproteins by mesangial cells. 840 82

Metabolites of arachidonic acid regulate several physiological processes, including vascular tone. The purpose of this study was to determine which metabolites of arachidonic acid are produced by bovine coronary arteries and which may regulate coronary vascular tone. Arachidonic acid induced a concentration-related, endothelium-dependent relaxation [one-half maximum effective concentration (EC50) of 2 x 10(-7) M and a maximal relaxation of 91 +/- 2% at 10(-5) M] of bovine coronary arteries that were contracted with U-46619, a thromboxane mimetic. The concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of prostaglandin I2 (PGI2), increased from 82 +/- 6 to 328 +/- 24 pg/ml with arachidonic acid (10(-5) M). Treatment with the cyclooxygenase inhibitor indomethacin attenuated arachidonic acid-induced relaxations by approximately 50% and blocked the synthesis of 6-keto-PGF1 alpha. PGI2 caused a concentration-related relaxation (EC50 of 10(-8) M and a maximal relaxation of 125 +/- 11% at 10(-7) M). BW755C, a cyclooxygenase and lipoxygenase inhibitor, inhibited arachidonic acid-induced relaxation to the same extent as indomethacin. When vessels were treated with both indomethacin and BW755C, the inhibition of relaxation was the same as either inhibitor alone. SKF 525a, a cytochrome P-450 inhibitor, reduced arachidonic acid-induced relaxation by approximately 50%. When SKF 525a was given in combination with indomethacin, the relaxation by arachidonic acid was almost completely inhibited. SKF 525a inhibited the synthesis of epoxyeicosatrienoic acids (EETs).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid. 844 48

Recent studies have demonstrated that unsaturated fatty acids are involved in the regulation of neuroeffector function. I have extended these studies by examining the effect of arachidonic acid on neuromuscular function in vitro using the rat phrenic nerve-diaphragm preparation. Arachidonic acid caused a time-and dose-dependent reduction in indirectly stimulated twitch tension, but had no effect on directly stimulated twitch tension. Linoleic acid and linolenic acid also reduced indirectly stimulated twitch tension, whereas stearic acid, oleic acid and arachidic acid had no effect. None of three blockers of arachidonic acid metabolism, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguaiaretic acid or the cytochrome P-450 inhibitor ketoconazole, altered the effect of arachidonic acid on twitch tension. The free radical scavenger superoxide dismutase eliminated the inhibitory effect of arachidonic acid on twitch tension, suggesting that superoxide anion played a role in arachidonic acid's action.
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PMID:Effect of arachidonic acid on twitch tension of the rat phrenic nerve-diaphragm. 845 Apr 67

Endothelial cells release several factors which influence vascular tone, leukocyte function and platelet aggregation. Some of these factors are metabolites of arachidonic acid, most notably prostacyclin. However, many of the endothelial metabolites of arachidonic acid have not been positively identified. The purpose of these studies is to identify the arachidonic acid metabolites synthesized by bovine coronary endothelial cells. Cultured bovine coronary artery endothelial cells were incubated with [14C]arachidonic acid. The incubation media was extracted and the radioactive metabolites resolved by a combination of reverse phase- and normal phase-high pressure liquid chromatography (HPLC). The cells synthesized 6-keto prostaglandin (PG)F1 alpha, PGE2, 12-hydroxyheptadecatrienoic acid (HHT), 12-, 15-, and 11-hydroxyeicosatetraenoic acids (HETE), and 14,15-, 11,12-, 8,9-, and 5,6-epoxyeicosatrienoic acids (EET). Several of the HETEs were further analyzed by chiral-phase HPLC. The cells synthesized predominately 12(S)-, 15(S)-, and 11(R)-HETE. The synthesis of the S optical isomers of 12- and 15-HETE suggested that the 12- and 15-lipoxygenases were present in these cells. 11(R)-HETE is probably derived from cyclooxygenase. They also synthesized smaller amounts of 9-, 8- and 5-HETEs. The structures of the HETEs and EETs were confirmed by mass spectrometry. The release of 6-keto PGF1 alpha and 15-HETE was measured by specific radioimmunoassays. Melittin, thrombin, arachidonic acid and A23187 stimulated the release of both eicosanoids in a concentration-related matter. Under all conditions, the release of 6-keto PGF1 alpha exceed the release of 15-HETE. Therefore, cultured bovine coronary artery endothelial cells synthesize cyclooxygenase, lipoxygenase and cytochrome P-450 metabolites of arachidonic acid.
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PMID:Synthesis of hydroxyeicosatetraenoic (HETEs) and epoxyeicosatrienoic acids (EETs) by cultured bovine coronary artery endothelial cells. 855 73

We have found that transient A-type currents expressed in Xenopus oocytes from members of the Kv4 family are suppressed by arachidonic acid. Currents from members of the Kv1, Kv2, and Kv3 families showed little or no inhibition by fatty acids in this expression system, although Shaker currents showed a modest increase in peak amplitude. The inhibition of Kv4 channels was not prevented by cyclo-oxygenase, lipoxygenase, or cytochrome P-450 inhibitors and was mimicked by 5,8,11,14-eicosatetraynoic acid, an arachidonic acid analog that is not metabolized by these pathways. Other unsaturated cis fatty acids with more than two double bonds produced a similar effect. In inside-out macropatches, the current was reversibly reduced > 50% by 2 mM arachidonic acid, and the inhibition developed in < 40 sec. These results suggest that, at concentrations that are likely to be physiologically relevant, arachidonic acid interacts directly with the channel or with a closely associated component. Preliminary mutagenesis of Kv4.2 channels indicates that the N terminal is not required for arachidonic acid action but that the S4-S5 loop may influence the effect.
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PMID:Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid. 855 29


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