Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat basophilic leukemia cells exhibit 12-lipoxygenase activity only upon cell disruption. 12-Lipoxygenase may also possess 15-lipoxygenase activity, as is indicated by the formation of low amounts of 15(S)-HETE, in addition to the predominant product 12(S)-HETE, upon incubation of partially purified 12-lipoxygenase with arachidonic acid. With 5(S)-HPETE as substrate not only 5(S), 12(S)-diHETE and 5(S), 15(S)-diHETE are formed, but also LTA4, as was indicated by the presence of LTA4-derived LTB4-isomers. 12-Lipoxygenase from rat basophilic leukemia cells has many features in common with 12-lipoxygenase from bovine leukocytes. As was suggested for the latter enzyme, 12-lipoxygenase from rat basophilic leukemia cells may represent the remaining LTA4-synthase activity of 5-lipoxygenase, of which the 5-dioxygenase activity has disappeared upon cell disruption. Such a possible shift from 5-lipoxygenase activity to 12-lipoxygenase activity could not simply be induced by interaction of cytosolic 5-lipoxygenase with a membrane fraction after cell disruption, but may involve release of membrane-associated 5-lipoxygenase upon disruption of activated rat basophilic leukemia cells.
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PMID:12-Lipoxygenase from rat basophilic leukemia cells, an oxygenase with leukotriene A4-synthase activity. 139 Aug 74

Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20,000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM), human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM, the compound produced little or no inhibition of several related enzymes, such as platelet 12-lipoxygenase, soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog, zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat, the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation, zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro, ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.
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PMID:5-lipoxygenase inhibitory activity of zileuton. 184 34

Clinical studies have indicated that dietary fish oil may have therapeutic value in the treatment of psoriasis, a hyperproliferative, inflammatory skin disorder characterized by elevated LTB4. To evolve a possible mechanism for these beneficial effects, we determined the metabolic fate of fish oil derived n-3 fatty acids in the skin. Specifically, we incubated guinea pig epidermal enzyme preparations with [3H]eicosapentaenoic acid (20:5 n-3) and [14C]docosahexaenoic acid (22:6 n-3). Analyses of the radiometabolites revealed the transformation of these n-3 fatty acids into n-6 lipoxygenase (arachidonate 15-lipoxygenase) products: 15-hydroxyeicosapentaenoic acid (15-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHE), respectively. Since 15-lipoxygenase products have been suggested as possible endogenous inhibitors of 5-lipoxygenase (an enzyme which catalyzes the formation of LTB4) we tested the ability of 15-HEPE and 17-HDHE in vitro to inhibit the activity of the 5-lipoxygenase. Incubations of these metabolites with enzyme preparations from rat basophilic leukemia (RBL-1) cells demonstrated that 15-HEPE (IC50 = 28 microM) and 17-HDHE (IC50 = 25 microM) are respectively potent inhibitors of RBL-I-5-lipoxygenase. The inhibitory potential of these fish oil metabolites provides a possible mechanism by which fish oil might act to decrease local cutaneous levels of LTB4, and thereby alleviate psoriatic symptoms.
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PMID:Guinea pig epidermis generates putative anti-inflammatory metabolites from fish oil polyunsaturated fatty acids. 255 81

We report the isolation and complete sequence of the gene encoding the rabbit erythroid-cell-specific 15-lipoxygenase (RBC 15-LOX), containing 14 exons spanning 8.0 kb. The transcription start point was mapped by S1 nuclease-protection experiments and comparison with the sequence of the RBC 15-LOX mRNA, as defined previously by primer extension experiments. The promoter contains a TATA-like motif, but no CCAAT motif in the canonical position, and lies within a 'CpG-rich island'. Functional analysis of the immediate 5'-flanking DNA by transfection experiments shows that a 150 nucleotide (nt) 5' fragment linked to the chloramphenicol acetyltransferase gene acts as a functional promoter in both erythroid and nonerythroid cell lines and responds in an erythroid-specific manner to the enhancer from the Friend murine leukaemia virus long terminal repeat, whereas a 40-nt fragment is inactive. Intron 7 contains eight copies of a 54-nt repeat containing a region with homology to the simian virus 40/immunoglobulin gene enhancers.
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PMID:The promoter structure and complete sequence of the gene encoding the rabbit erythroid cell-specific 15-lipoxygenase. 261 16

The enzyme responsible for 15-lipoxygenation of arachidonic acid was purified to homogeneity from human eosinophil-enriched leukocytes using a combination of ammonium sulfate precipitation, hydrophobic interaction chromatography, and high pressure liquid chromatography on hydroxyapatite and cation-exchange columns. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified protein revealed a single major band (apparent Mr 70,000). Amino acid sequence analysis yielded a single N-terminal sequence. Comparison of the N-terminal 15 residues reveals 71% sequence identity to the rabbit reticulocyte lipoxygenase and 36% sequence identity to the rat basophilic leukemia 5-lipoxygenase. In contrast, sequence identity to the soybean lipoxygenase-1 is not observed. These results demonstrate that human 15-lipoxygenase can be isolated from eosinophil-enriched leukocytes and is accessible for direct sequence analysis. Furthermore, we present initial evidence that the mammalian lipoxygenases constitute an homologous family of enzymes. The availability of homogeneous human 15-lipoxygenase will play a key role in elucidating other relationships in this family of enzymes.
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PMID:Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases. 335 88

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

Leukotriene A4 hydrolase is a bifunctional metalloenzyme that contains 1 mol of zinc per mole of protein. The primary function of the metal is catalytic and zinc is thus necessary for both its peptidase and its epoxide hydrolase activity. However, at concentrations of zinc exceeding a 1:1 molar ratio (metal:enzyme), we found that zinc acted as an inhibitor with IC50 values of 10 microM for the epoxide hydrolase activity, i.e., the conversion of leukotriene A4 to leukotriene B4, and 0.1 microM for the peptidase activity. The inhibition of both enzyme activities could be reversed by treating the enzyme with chelating agents such as EDTA or dipicolinic acid. Several divalent cations, other than zinc, were also found to inhibit leukotriene A4 hydrolase although with different specificity and potency for the two enzyme activities. Thus, CdSO4 and HgCl2 were effective inhibitors (IC50 approximately 10 microM) of the epoxide hydrolase activity, whereas CoCl2 or MnCl2 were not inhibitory even at concentrations of 1 mM. On the other hand, the peptidase activity was inhibited by CdSO4, NiSO4, HgCl2, MnCl2, CoCl2, and PbNO3, listed in decreasing order of potencies (IC50 0.5-10 microM). In addition, zinc in micromolar concentrations inhibited leukotriene B4 formation in intact human polymorphonuclear leukocytes stimulated by the calcium ionophore A23187 and cell homogenates incubated with arachidonic acid. However, this effect was not related to inhibition of leukotriene A4 hydrolase but rather to a direct or indirect inhibitory effect on the enzyme 5-lipoxygenase in isolated leukocytes. In these cells, 15-lipoxygenase activity was also inhibited by zinc (IC50 5 microM), whereas leukotriene C4 synthase activity in human platelets and rat basophilic leukemia cells was significantly affected only at concentrations > or = 1 mM.
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PMID:Zinc and other divalent cations inhibit purified leukotriene A4 hydrolase and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes. 820 89

5-Lipoxygenase has been recognized to be an important enzyme that catalyzes the first step in leukotriene production. In this study we examine whether or not phospholipids containing docosahexaenoic acid (DHA) affect 5-lipoxygenase activity of a rat basophilic leukemia cell line (RBL-1). Among the synthesized phospholipids examined, 1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (1-oleoyl-2-DHA-PC) was found to be the most potent inhibitor of 5-lipoxygenase. The inhibition was dose-dependent and the ID50 value was 4.0 microM. When the fatty acid at the sn-2-position was replaced by other unsaturated fatty acids, the inhibitory activity decreased with decreasing numbers of both carbon atoms and double bonds in the fatty acids. Substitution at the 1-position of the DHA-containing PC also affected the inhibitory potency. If oleic acid was substituted with palmitic acid, the inhibition activity was completely abolished. Lineweaver-Burk plot analysis showed that the inhibition of 5-lipoxygenase by 1-oleoyl-2-DHA-PC was non-competitive. The inhibition by this synthesized phospholipid was very specific to 5-lipoxygenase; that is, it did not extend to fatty acid cyclooxygenase, 12-lipoxygenase or 15-lipoxygenase. These results suggest that endogenously existing DHA-containing phospholipids may affect 5-lipoxygenase activity and thus control leukotriene biosynthesis in vivo.
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PMID:Inhibitory effect of docosahexaenoic acid-containing phospholipids on 5-lipoxygenase in rat basophilic leukemia cells. 830 21

A novel compound termed YT-18 (2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperazinyl) methyl]-5-benzofuranamine) selectively inhibited 5-lipoxygenases of porcine leukocytes (IC50 value, 7.5 microM), human leukocytes (1.5 microM), and rat basophilic leukemia cells (14 microM), which are responsible for bioactive leukotriene synthesis. In contrast, the compound up to 1 mM had almost no effect on 12-lipoxygenases of leukocytes and platelets, 15-lipoxygenase, and cyclooxygenases-1 and -2. YT-18 also inhibited the leukotriene synthesis in intact rat basophilic leukemia cells. In the 5-lipoxygenase reaction, YT-18 caused a lag phase, thereby delaying the start of the reaction. The lag was abolished by the addition of 13-hydroperoxy-linoleic acid in a dose-dependent manner, and most (but not all) of the reduced 5-lipoxygenase activity was recovered.
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PMID:A selective inhibitor of arachidonate 5-lipoxygenase scavenging peroxide activator. 931 81

The ubiquitous hydroxylated fatty acids derived from arachidonic acid (HETEs) or linoleic acid (HODEs) exhibit diverse biological effects including chemotaxis, cell proliferation, and modulation of several enzymatic pathways, including the 5-lipoxygenase leading to the inflammatory leukotrienes. It was observed that 12(S)- and 15(S)-HETE and 13(S)-HODE (12- and 15-lipoxygenase-derived metabolites, respectively) inhibited the 5-lipoxygenase present in rat basophilic leukemia (RBL-1) cell homogenates whereas the 15(R) chiral enantiomer and the nonhydroxylated linoleic, oleic, and stearic acids were either less potent or ineffective. In examining the mechanism of this inhibition, the relative effectiveness of several fatty acids in displacing [3H]15-HETE bound to cytosol preparations were compared and the results indicated that these (S) hydroxy fatty acids and 5(S)-HETE were significantly more potent than either the 15(R) enantiomer, 15(S)-HETE methyl ester, arachidonic acid, or prostaglandin F2alpha. In order to identify the protein(s) that specifically binds HETEs, 15(S)-HETE biotin hydrazide was used as a probe to detect any HETE-protein complexes as this compound both inhibited the 5-lipoxygenase and interfered with the binding of [3H]15-HETE to cytosol preparations. SDS-PAGE analysis and chemiluminescent detection revealed that the major cytosolic proteins that bound this biotinylated probe had molecular masses of 43 and 51 kD. Fatty acid competition experiments indicated that the order of effectiveness in displacing this probe from these proteins was 13(S)-HODE > 5(S)-HETE approximately equal to 15(S)-HETE > > stearic acid approximately equal to arachidonic acid approximately equal to 15(R)-HETE. Amino acid sequence analysis showed that the 43 kD protein was actin. These findings suggest the possibility that actin may play a major role in the biological effects of monohydroxylated metabolites derived from cellular 5-, 12-, and 15-lipoxygenases.
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PMID:Mono (S) hydroxy fatty acids: novel ligands for cytosolic actin. 968 51


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