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)

The release of slow reacting substance (SRS) from rat basophilic leukemia cells (RBL-1) by the ionophore A23187 (5-10 mug/ml) was stimulated 5-fold by arachidonate and inhibited 78% by 5,8,11,14-eicosatetraynoate (an inhibitor of both fatty acid cyclooxygenase and lipoxygenase). Linoleic acid and linolenic acid both inhibited SRS formation, whereas indomethacin (a cyclooxygenase inhibitor) had no effect. Radiolabel from [14C]- or [3H]arachidonate was incorporated into SRS as indicated by comigration of radioactivity and bioreactivity in several chromatographic systems after purification to apparent radiochemical homogeneity. The radiolabeled SRS was clearly separated chromatographically from other known arachidonate metabolites. Thus, SRS appears to be a previously undescribed product of arachidonic acid metabolism, probably formed through the lipoxygenase pathway. The ability to prepare purified, biosynthetically labeled, SRS should be of considerable help in further studies of its structure, biologic function, and catabolism.
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PMID:Precursor role of arachidonic acid in release of slow reacting substance from rat basophilic leukemia cells. 2 78

The most prominent slow reacting substance from rat basophilic leukemia cells (type I) was characterized by radiochemical, chemical and physical methods and shown to contain a C20 unsaturated fatty acid oxygenated at the 5 position and a sulfur containing side chain in thioether linkage at the 6 position. Its spasmogenic action on guinea pig ileal muscle was largely inactivated under reducing conditions which suggested that a peroxy group was present and important for contractile activity. This was supported by ferrous thiocyanate analysis. The peroxy group is almost certainly at the 5 position, probably in the form of a peroxy ester or hydroperoxide. Based on amino acid hydrolysis (0.85 moles of glycine and 0.30 moles of glutamic acid per mole SRS), the sulfur containing side chain is apparently a mixture of glutathione and cysteinyl-glycine, but by chromatography the side chain is predominantly glutathione and the low yield of glutamic acid may be due to complexing of its alpha COOH group in a peroxy ester linkage. The fatty acid moiety has 3 conjugated double bonds, probably at the 7,8, 9,10 and 11,12 positions. Type II SRS, the second major species, differs in that the sulfur containing side chain is linked at the 12 or 13 position and is almost certainly glutathione and in the failure of alkaline borohydride to produce inactivation. These observations strongly implicate the lipoxygenase pathway in slow reacting substance biosynthesis.
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PMID:Characterization of the two major species of slow reacting substance from rat basophilic leukemia cells as glutathionyl thioethers of eicosatetraenoic acids oxygenated at the 5 position. Evidence that peroxy groups are present and important for spasmogenic activity. 4 77

The generation of slow reacting substance (SRS) from ionophore A23187-stimulated rat peritoneal mast cells was enhanced by arachidonic acid (AA). This SRS generation was inhibited by 5,8,11,14-eicosatetraynoic acid (ETYA), an acetylenic analogue of AA and an inhibitor of both fatty acid cyclooxygenase and lipoxygenase. Indomethacin, a fatty acid cyclooxgenase inhibitor, had an enhancing effect upon SRS generation. This suggests SRS generation occurred through an ETYA sensitive step--perhaps a lipoxygenase. Radiolabel from [14C]-AA was incorporated into SRS with comigration of radioactivity and bioreactivity in silicic acid and thin layer chromatographies. Upon silicic acid chromatography, the active principle was eluted in the methanol fraction. Two-dimensional thin layer chromatography revealed chromatographic separation from other known spasmogenic substances and phospholipids. Mast cell SRS was found to display physiochemical properties similar to those of rat basophilic leukemia cell SRS, namely: that mast cell SRS generation was 1) enhanced by arachidonic acid; 2) inhibited by ETYA but not by indomethacin; 3) incorporation of [14C]-AA into the active principle; and 4) similar behavior during purification in silicic acid and thin layer chromatographies.
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PMID:Slow reacting substance (SRS) from ionophore A23187-stimulated peritoneal mast cells of the normal rat. II. Evidence for a precursor role of arachidonic acid and further purification. 37 31

Basophils located in tissues are called mast cells and are found in connective tissue. Many different compounds are secreted from basophil granules upon appropriate stimulation. Products such as heparin, histamine, serotonin (5-hydroxytryptamine, 5-HT), and membrane-derived materials which give rise to arachidonic acid metabolites, such as prostaglandins and leukotrienes, are some of the more important compounds released by mast cells. These compounds, when released after stimulation with a variety of molecules, such as IgE, specific antigen anaphylotoxin, as well as the compound 48/80 (C48/80) or calcium ionophore A23187, cause contraction of endothelial cells and mediate atopic or anaphylactic hypersensitivity. In this report, we study the generation of some arachidonic acid products, namely leukotrienes C4, D4, E4, and B4 and the prostaglandins D2 and E2 by rat peritoneal mast cells (RPMC), using calcium ionophore A23187 as a degranulating agonist. We have also studied the new lipoxygenase products, lipoxins A4 and B4, on RPMC secretion using C48/80 as a secretagogue. A rat basophilic leukemia cell line (RBL) was also used to compare results with RPMC. In this paper we have demonstrated that RPMC stimulated with A23187 release LTC4, LTD4, LTE4 and LTB4 and also PGD2 but not PGE2. These results were also confirmed when RBLs were used. In addition, we have shown that mast cells pretreated with LTC4, LTD4, LTE4 or 15-HETE do not modify the release of [3H]5HT exerted by C48/80 (0.5 microgram/ml) or A23187 (5 micrograms/ml). When LXA4 or B4 was used, mast cells were inhibited slightly (not statistically significant) from degranulating after the secretagogue treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of lipoxins A4 and B4 in the generation of arachidonic acid metabolites by rat mast cells and their effect on [3H]serotonin release. 161 34

To elucidate the differentiation-associated expression of enzymes catalyzing arachidonic acid metabolism, we measured arachidonate metabolites by reverse-phase high pressure liquid chromatography in monocytoid leukemia (ML-1, THP-1, and U937) and myeloid leukemia (KG-1) cell lines. Undifferentiated ML-1 or THP-1 cells produced trace amounts of eicosanoids via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Upon differentiation induced by phorbol ester (phorbol 12-myristate 13-acetate [PMA]), metabolites via the COX pathway were increased by 100-fold in ML-1 and THP-1 cells, while the LOX products remained barely detectable. All the COX metabolites were elevated, but thromboxane A2 (TXA2) formation was threefold higher in ML-1 cells than in THP-1 cells. Similar time-related increases in COX metabolites were observed in THP-1 cells induced to differentiate with retinoic acid. Undifferentiated U937 cells were capable of generating a much higher quantity of COX products than ML-1 or THP-1 cells, but, upon PMA-induced differentiation, COX products were increased by only two-fold to threefold over the undifferentiated cells and the total COX products in differentiated U937 cells were only one-seventh of those produced by differentiated ML-1 or THP-1 cells. KG-1 cells had an entirely different metabolic profile. They produced a large quantity of a metabolite coeluted with prostaglandin D2, and PMA had no effect on inducing changes in arachidonic acid (AA) metabolism. Increased COX metabolite formation in differentiated THP-1 and ML-1 cells was due to an enhanced level of prostaglandin H synthase enzyme mass, as measured by Western blot analysis. The TXA synthase activity was also increased by approximately 100-fold in PMA-induced ML-1 cells and 10-fold in THP-1 cells. These findings indicate that increased expression of prostaglandin H and TXA synthase enzymes is a feature of differentiated monocytoid leukemia cell lines.
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PMID:Differentiation-associated expression of prostaglandin H and thromboxane A synthases in monocytoid leukemia cell lines. 174 85

Sodium vanadate (11 microM) amplified the PGI2 production of rat liver cells (the C-9 cell line) incubated with thrombin, platelet activating factor, lysine-vasopressin, the Ca2(+)-ionophore A-23187, interleukin-1 beta, 12-tetradecanoylphorbol-13-acetate, teleocidin, epidermal growth factor, palytoxin, thapsigargin and colchicine but not that stimulated by exogenous arachidonic acid. Sodium vanadate (2.2 microM) also amplified PGF2 alpha production of dog kidney cells (the MDCK cell line) incubated with norepinephrine and, at 0.4 microM, PGI2 production of bovine aorta smooth muscle cells stimulated by serotonin. Sodium vanadate (55 microM) did not affect production of PGE2 and PGF2 alpha in rat basophil leukemia cells (the RBL-1 cell line) stimulated by the Ca2(+)-ionophore A-23187, but did inhibit synthesis of peptide-containing leukotrienes and 12-hydroxyeicosatetraenoic acid. When used with cultured cells at micromolar concentrations, vanadate is known to inhibit protein tyrosine-phosphate phosphatases. These results suggest that in some cells deesterification of lipids is positively regulated, at least in part, by phosphorylation of tyrosine whereas in leukocytes, lipoxygenase activities are negatively regulated, at least in part, by phosphorylation of tyrosine.
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PMID:Actions of vanadate on arachidonic acid metabolism by cells in culture. 202 Jul 48

Incubation of rat basophilic leukemia cells with exogenous arachidonic acid and permeabilizing concentrations of ethanol resulted in the production of 5-, 12-, and 15-hydroxyeicosatetraenoic acids. With chiral phase high performance liquid chromatography, it was demonstrated that the 5-hydroxyeicosatetraenoic acid had strict (S) stereospecificity while contrary to expectation, the 12- and the 15-hydroxyeicosatetraenoic acids were non-racemic mixtures of the stereoisomers with the S/R ratios averaging 8.6 and 2.2, respectively. If the strict (S) stereospecificity of mammalian lipoxygenases holds true, these results suggest that the 15- and 12-hydroxyeicosatetraenoic acids may be derived from non-lipoxygenase sources. Examination of the chirality of the oxygenase products of unsaturated fatty acids may be of value in defining the enzymes which are activated in vivo in pathological states.
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PMID:Characterization of the chirality of the monohydroxy-eicosatetraenoic acids produced by rat basophilic leukemia cells. 211 79

We have examined the effects of various inhibitors of the lipoxygenase pathway of arachidonic acid metabolism on the growth of three well-characterized human leukemia cell lines, HL-60, K-562, and KG-1. An intact lipoxygenase pathway, and the synthesis of leukotriene C4 (LTC4), which requires reduced glutathione, is essential for in vitro growth of normal myeloid progenitors (CFU-GM). We tested the effects of nordihydroguiaretic acid (NDGA) and caffeic acid (CA), inhibitors of lipoxygenase; buthionine sulfoximine (BSO), which inhibits glutathione synthesis; and Acivicin, a glutamine antagonist, on these cell lines and compared the effects with those seen on CFU-GM. In semisolid culture, all three cell lines were inhibited by NDGA, CA, and BSO in a dose-dependent manner similar to that in CFU-GM but were relatively resistant to Acivicin. In liquid culture, all three cell lines exhibited relative resistance to inhibition by both BSO and Acivicin, with KG-1 also demonstrating relative resistance to inhibition by NDGA and CA. The inhibition of HL-60 by CA could be completely reversed by the addition of exogenous leukotriene D4. The dependence on the lipoxygenase pathway may be altered to varying degrees in different leukemic lines and may depend on culture conditions. Whether these changes may contribute to the pathogenesis of leukemia or merely represent secondary metabolic changes is yet to be determined.
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PMID:Effects of lipoxygenase and glutathione pathway inhibitors on leukemic cell line growth. 249 78

Essential thrombocythaemia (ET) is a rare clonal myeloproliferative disorder characterized by a persistent increase in platelet count. The commonly used criteria for the diagnosis, except for the level of the increase in platelet count, are usually those fixed by the Polycythemia Vera Study Group. The average age of onset is around 60 years, both sexes being affected. The symptoms frequently present at diagnosis are related to microcirculatory disturbances (palms, soles, fingers). Neurological symptoms are often observed. Thrombotic complications of the large vessels are less frequent. Haemorrhagic problems are present in about 30% of patients. Bleeding time is normal in most cases, whereas platelet aggregation abnormalities are frequently found. Nil adrenaline aggregation is the most discriminative test. The clinical course is characterized by long intervals without any symptoms; thromboembolic or haemorrhagic episodes can, however, occur, mainly in uncontrolled ET. Development of terminal acute leukaemia has been reported in 34 cases. The expression of the influence of the treatments, 32P or alkylating agents, is very strong. The treatment of ET has to take in consideration the difficult compromise between balancing the necessity of preventing complications and the effects of drug toxicity. The use of recombinant alpha-interferon has recently been proposed and is under investigation. The pathogenesis of thrombocytosis in ET seems to involve an expansion in the megakaryocyte progenitor cell pool. Platelet membrane glycoprotein abnormalities and defective glycosylation of thrombospondin have been shown. Numerous other platelet abnormalities, including decreased alpha-adrenergic receptors, loss of PGD2 receptors and increased Fc receptors, have been reported. Arachidonic metabolism seems to be abnormal and lipoxygenase is defective. Most of the platelet abnormalities seem to be the result of intrinsic defects at the level of an abnormal clone of megakaryocytes. However, causal relationships between the platelet abnormalities and bleeding or thrombosis are not yet clearly demonstrated.
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PMID:Essential thrombocythaemia. 250 75

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


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