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)

Both polymorphonuclear (PMN) leukocytes and metabolites of arachidonic acid, especially lipoxygenase products, have been reported to contribute to myocardial damage after coronary artery occlusion and reperfusion. While canine models of myocardial ischemia were used in many of these studies, very little is known about arachidonic acid metabolism by canine PMNs. Moreover, it is unclear whether arachidonic acid metabolites released by canine PMNs affect vascular tone. Therefore, we characterized arachidonic acid metabolism by canine PMNs and determined the effect of these metabolites on vascular tone of isolated canine coronary arteries. Suspensions of canine PMNs were incubated with [14C]arachidonic acid and the calcium ionophore A23187. The incubation media was extracted, and the metabolites resolved by HPLC. 20-Hydroxy-leukotriene B4 (LTB4), 12,20-dihydroxyeicosatetraenoic acid (diHETE), LTB4, 12-hydroxyheptadeclatrienoic acid (HHT), and 12-(S)-hydroxyeicosatetraenoic acid (HETE) were isolated, and their structures confirmed by gas chromatography/mass spectrometry. There was also evidence for the formation of 20-HETE, thromboxane B2 (TXB2), 5-HETE, and several isomers of LTB4. None of the arachidonic acid metabolites that were isolated from incubates of canine PMNs augmented vascular tone, but material migrating with 12,20-diHETE relaxed canine coronary arteries. Authentic 12(S),20-diHETE also produced a concentration-related relaxation of canine coronary artery. 12(R), 20-diHETE was inactive. 20-HETE inhibited A23187-induced PMN aggregation. Thus, arachidonic acid is metabolized in canine PMNs through the cyclooxygenase, lipoxygenases and cytochrome P-450 pathways. Whether these metabolites contribute to myocardial injury remains to be determined.
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PMID:Metabolism of arachidonic acid by canine polymorphonuclear leukocytes synthesis of lipoxygenase and omega-oxidized metabolites. 865 40

Treatment of 3T3-L1 preadipocytes with arachidonic acid resulted in a dose-dependent inhibition of adipocyte differentiation. The cells failed to accumulate fat droplets and did not express stearoyl-CoA desaturase 1 mRNA, a marker for late-stage differentiation. The inhibition of differentiation was reversed by the addition of cyclooxygenase inhibitors ibuprofen or indomethacin. Inhibitors of the lipoxygenase and cytochrome P-450 epoxygenase pathways were unable to reverse the effect of arachidonic acid. Dexamethasone, one of the adipogenic agents normally used to induce differentiation, could be replaced with cyclooxygenase inhibitors in the differentiation cocktail. This implicated dexamethasone as a modulator of prostaglandin synthesis in culture. Prostaglandins F2 alpha (ED50 = 0.4 nM), E2, and D2 prevented differentiation, each with a specific, dose-dependent affinity. Prostaglandin F2 alpha was the most potent inhibitor of differentiation, suggesting that a prostanoid FP2 receptor (FP receptor) mediates the prostaglandin action. Fluprostenol (ED50 = 0.3 nM), a selective FP receptor agonist, prevented differentiation, confirming the involvement of an FP receptor in the inhibition of 3T3-L1 preadipocyte differentiation. Stimulation of the FP receptor for 1 h during the first day of differentiation was sufficient to cause substantial inhibition. Endogenous PGF2 alpha production was lower in differentiating cells compared to unstimulated preadipocytes. These data suggest that PGF2 alpha production by preadipocytes plays a role in maintaining the undifferentiated state.
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PMID:Preadipocyte differentiation blocked by prostaglandin stimulation of prostanoid FP2 receptor in murine 3T3-L1 cells. 876 50

2-Hydroxy-5-methyl-laurophenone-oxime (FLM 5011, 1) is an inhibitor of the lipoxygenase with antiinflammatory and antiallergic actions. The studies on the biotransformation using in vivo investigations and in vitro test systems resulted in finding of at least eight metabolites. Four of these compounds have been detected and identified in urine and faeces after p.o. administration in male Wistar rats. By means of cultures of hepatocytes, lymphocytes and myeloma cells additional metabolites were found and the main pathways of metabolism could be suggested. Furthermore it was possible to confirm the sequence of the metabolic reactions. First of all, 1 is hydroxylated in the omega-position of the lauryl side chain by the cytochrome P-450 system. The further oxidation to the carboxylated compound is followed by the stepwise degradation of the side chain by beta-oxidation similarly to the pathways of fatty acid metabolism. Simultaneously the oxime group is converted to the keto group. The metabolites and 1 partly occur as sulfate or glucuronide conjugates. Additionally all compounds produced by beta-oxidation are conjugated with other partners, probably amino acids. By omega-oxidation, compounds with higher inhibitory potency on the lipoxygenase than the parent compound are formed. These results suggest that the activity of 1 is partly caused by the initial metabolites.
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PMID:[Biotransformation of the lipoxygenase inhibitor 2-hydroxy-5-methyl-laurophenone-oxime (FLM 5011)]. 876 50

Arachidonic acid elicited relaxation responses in normal rabbit aorta precontracted with norepinephrine. The relaxation response was enhanced by the cyclooxygenase inhibitor indomethacin and inhibited by lipoxygenase inhibitors, including nordihydroguaiaretic acid and cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. The cytochrome P-450 epoxygenase inhibitor metyrapone had no effect on arachidonic acid-induced relaxations. The present study hypothesized that a lipoxygenase metabolite of arachidonic acid mediated the response. Incubation of rabbit aorta with [14C]arachidonic acid resulted in the synthesis of a previously unidentified 14C-labeled metabolite and was called the unknown factor. Production of the unknown factor was not inhibited by indomethacin and decreased by lipoxygenase inhibitors. Production of the unknown factor and arachidonic acid-induced relaxations were dependent on an intact endothelium, indicating that the cellular source of the unknown relaxant factor was the endothelial cell. This was confirmed by demonstrating the ability of cultured rabbit aortic endothelial cells to produce the unknown factor from [14C]arachidonic acid. Feeding rabbits a 2% cholesterol diet for 2 wk induced hypercholesterolemia without causing atherosclerosis. In the cholesterol-fed rabbits, indomethacin enhanced arachidonic acid-induced relaxations in norepinephrine-precontracted aortas (maximal relaxation 49.0 +/- 2.5 vs. 35.5 +/- 1.7%, cholesterol-fed vs. normal) and increased production of the unknown factor compared with normal rabbits. The partially purified unknown factor elicited an approximately 26% inhibition of the vasoconstrictor response to norepinephrine in intact rabbit aorta. Further purification of the unknown factor by reverse-phase high-pressure liquid chromatography system resulted in isolation of a radioactive product that relaxed precontracted rabbit aorta. Therefore these data suggest that in normal and hypercholesterolemic rabbit aorta the endothelium produces an unknown metabolite of arachidonic acid that causes vasorelaxation and may regulate vascular tone.
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PMID:Vasorelaxation by an endothelium-derived metabolite of arachidonic acid. 878 Jan 99

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 microM 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. 878 28

Arachidonic acid (AA) has been shown to inhibit the activity of the low-conductance ATP-sensitive K+ channel in the apical membrane of the cortical collecting duct [W. Wang, A. Cassola, and G. Giebisch. Am. J. Physiol. 262 (Renal Fluid Electrolyte Physiol. 31): F554-F559, 1992]. ROMK1, a K+ channel derived from the rat renal outer medulla, shares many biophysical properties of the native low-conductance K+ channel, which is localized to the apical membranes of the cortical collecting duct and thick ascending limb. This study was designed to determine whether the ROMK channel maintains the property of AA sensitivity of the native low-conductance K+ channel. Experiments were conducted in Xenopus oocytes injected with cRNA encoding the ROMK1 channel by use of patch-clamp techniques. We have confirmed previous reports that the cloned ROMK1 has similar channel kinetics, high open probability, and inward slope conductance as the native low-conductance K+ channel, respectively. Addition of 5 microM AA to an inside-out patch resulted in reversible inhibition of channel activity at a concentration similar to the inhibitor constant for AA on the native K+ channel. The effect of AA on channel activity was preserved in the presence of 10 microM indomethacin, a cyclooxygenase inhibitor, 4 microM cinnamyl-3,4-dihydroxycyanocinnamate, a lipoxygenase inhibitor, and 4 microM 17-octadecynoic acid, an inhibitor of cytochrome P-450 monooxygenases, thus indicating that the effect of AA was not mediated by metabolites of AA. The effect did not appear to be the result of changes in membrane fluidity, since 5 microM eicosatetraynoic acid, an AA analogue that is a potent modulator of membrane fluidity, had no effect. Furthermore, the addition of AA to the outside of the patch also had no effect on channel activity. These results indicate that, like the native low-conductance channel, AA is able to directly inhibit ROMK1 channel activity.
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PMID:Arachidonic acid inhibits activity of cloned renal K+ channel, ROMK1. 885 20

The neutrophil respiratory burst was examined by the technique of luminol-dependent chemiluminescence (LDCL) triggered by submaximal concentrations of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in diluted whole blood. We sought to identify the chemical species responsible for LDCL in whole blood, to examine the role of leukotriene B4 (LTB4) and other arachidonic acid metabolites as mediators of the fMLP signaling pathway, and to investigate the effect of peroxynitrite on this response. Both sodium azide and taurine significantly inhibited LDCL (93% inhibition with 100 microM azide, 52% inhibition with 10 mM taurine). More modest inhibition was seen with superoxide dismutase (SOD), catalase, the nitric oxide synthase inhibitor monomethyl-L-arginine (L-NMMA), and with inhibitors of the cyclooxygenase (indomethacin), lipoxygenase (AA-861; no effect), and cytochrome P-450 (SKF 525-A) pathways of arachidonic acid metabolism. The nitric oxide donor SIN-1 (1-100 microM) and peroxynitrite (10-300 microM) also augmented fMLP-induced LDCL. The augmentation seen with peroxynitrite and SIN-1 was attenuated by SOD. Despite the increase in LDCL, peroxynitrite caused a dose-related inhibition of fMLP-stimulated LTB4 release. In summary, our results indicate that (1) LDCL elicited by fMLP in diluted whole blood appears primarily mediated by hypochlorous acid derived from myeloperoxidase; (2) pretreatment with the nitric oxide donor SIN-1 or with peroxynitrite augments LDCL; and (3) LTB4 release does not contribute to fMLP-stimulated LDCL or in the modulation of LDCL by SIN-1 or peroxynitrite.
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PMID:Peroxynitrite augments fMLP-stimulated chemiluminescence by neutrophils in human whole blood. 892 53

The effects of arachidonic acid (20:4, n-6) and other fatty acids on the expression of stearoyl-CoA desaturase gene 1 were investigated in fully differentiated 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with arachidonic acid resulted in a decrease in stearoyl-CoA desaturase (Scd) enzyme activity and scd1 mRNA. Arachidonic acid did not alter the transcription of the scd1 gene, whereas the half-life of the scd1 mRNA was reduced from 25.1 to 8.5 h. Blocking the conversion of arachidonic acid to eicosanoids by pretreatment of the cells with cyclooxygenase, lipoxygenase, or cytochrome P-450 epoxygenase inhibitors did not reverse the inhibition caused by arachidonic acid, indicating that eicosanoid synthesis is not necessary for the repression of scd1 mRNA expression. Treatment of adipocytes with linoleic (18:2, n-6) and linolenic (18:3, n-3) acids also resulted in inhibition of scd1 mRNA accumulation. By contrast, oleic acid (18:1, n-9) and stearic acid (18:0) had no effect on scd1 mRNA levels. Taken together, these results suggest that polyunsaturated fatty acids repress the expression of the scd1 gene in mature adipocytes by reducing the stability of scd1 mRNA.
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PMID:Regulation of stearoyl-CoA desaturase 1 mRNA stability by polyunsaturated fatty acids in 3T3-L1 adipocytes. 893 25

Manganese enhanced atrazine transformation by the fungus Pleurotus pulmonarius when added to a liquid culture medium at concentrations of up to 300 microM. Both N-dealkylated and propylhydroxylated metabolites accumulated in the culture medium, with the former accumulating to a greater extent than did the latter. Lipid peroxidation, oxygenase and peroxidase activities, and the cytochrome P-450 concentration increased. In addition, an increase in the spectral interactions between atrazine and components in the cell extract was observed. Antioxidants, mainly nordihydroguaiaretic acid, which inhibits lipoxygenase, peroxidase, and P-450 activities, and piperonyl butoxide, which inhibits P-450 activity, inhibited atrazine transformation by the mycelium. It is suggested that the stimulation of oxidative activity by Mn might be responsible for increasing the biotransformation of atrazine and for nonspecific transformations of other xenobiotic compounds.
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PMID:Manganese-enhanced biotransformation of atrazine by the white rot fungus Pleurotus pulmonarius and its correlation with oxidation activity. 896 73

In addition to being a potent hepatocarcinogen, aflatoxin B1 (AFB1) is a pulmonary carcinogen in experimental animals, and epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. This study investigated AFB1 bioactivation and detoxification in human lung tissue obtained from patients undergoing clinically indicated lobectomy. [3H]AFB1 was bioactivated to a DNA binding metabolite by human whole lung cytosols in a time-, protein concentration-, and AFB1 concentration-dependent manner. Cytosolic activation of [3H]AFB1 correlated with lipoxygenase (LOX) activity and was inhibited by the LOX inhibitor nordihydroguaiaretic acid (NDGA; 100 microM), indicating that LOXs were largely responsible for the observed cytosolic activation of AFB1. In whole lung microsomes, low levels of indomethacin inhibitable prostaglandin H synthase (PHS)-mediated [3H]AFB1-DNA binding and cytochrome P-450 (P450)-mediated [3H]AFB1-DNA binding were observed. Cytosolic glutathione S-transferase (GST)-catalyzed detoxification of AFB1-8,9-epoxide, produced by rabbit liver microsomes, was minimal at 1 and 10 microM [3H]AFB1. With 100 microM [3H]AFB1, [3H]AFB1-8,9-epoxide conjugation with reduced glutathione was 0.34 +/- 0.26 pmol/mg/h (n = 10). In intact, isolated human lung cells, [3H]AFB1 binding to cellular DNA was higher in cell fractions enriched in macrophages than in either type II cell-enriched fractions or fractions containing unseparated cell types. Indomethacin produced a 63-100% decrease in [3H]AFB1-DNA binding in macrophages from five of seven patients, while NDGA inhibited [3H]AFB1-DNA adduct formation by 19, 40 and 56% in macrophages from three of seven patients. In alveolar type II cells, NDGA decreased [3H]AFB1-DNA binding by 30-100% in cells from three patients and indomethacin had little effect. SKF525A, an isozyme non-selective P450 inhibitor, enhanced [3H]AFB1 binding to cellular DNA in unseparated cells, macrophages, and type II cells, suggesting that P450-mediated bioactivation of AFB1 is not a major pathway by which AFB1-8,9-epoxide is formed in human lung cells. Overall, these studies suggest that P450 has a minor role in the bioactivation of AFB1 in human lung. Rather, LOXs and PHS appear to be important bioactivation enzymes. Co-oxidative bioactivation of AFB1, in combination with the low conjugating activity displayed by human lung cytosolic GSTs, likely contributes to human pulmonary susceptibility to AFB1.
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PMID:Biotransformation of aflatoxin B1 in human lung. 896 67


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