Effects of a 5-lipoxygenase inhibitor, AA861, on lipoxygenase metabolism and superoxide anion generation by human polymorphonuclear leukocytes--potentiation of superoxide anion generation by LTB4. 1992

K Tanaka, and M Abe, and N Shigematsu
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

We studied the influence of a selective 5-lipoxygenase inhibitor, AA861, on the generation of the superoxide anion (O2-) and the lipoxygenase metabolites by human polymorphonuclear leukocytes (PMN). PMN produce O2- in a dose-dependent manner following stimulation with arachidonic acid (AA), leukotriene B4 (LTB4), or C5a. When PMN were stimulated with one of those three agents in the presence of high doses of AA861 (1-10 micrograms/ml), a significant reduction of O2- release was observed. In contrast, the generation of O2- by PMN stimulated by LTB4 was potentiated at lower concentrations of AA861 (0.025-0.25 micrograms/ml). However, stimulation with AA or C5a did not influence O2- generation in the presence of AA861 at the same concentration range. Furthermore, treating the PMN with the cyclooxygenase inhibitor, acetylsalicylic acid, did not potentiate the generation of O2- by stimulation with LTB4 over a wide range of concentrations. Quantification of lipoxygenase metabolites by reverse-phase high-performance liquid chromatography revealed that a high concentration of AA861 (0.5-5 micrograms/ml) completely inhibited the production of LTB4 and its omega-oxidative metabolites by PMN following stimulation with 100 microM AA, but only partially inhibited that of 5-hydroxyeicosatetraenoic acid (5-HETE). AA861 at a concentration of 5 micrograms/ml significantly increased the production of 15-HETE by PMN following the same stimulation. AA861 did not influence catabolism of LTB4 added to the reaction mixture to its omega-oxidative products by PMN over a wide range of concentrations. These findings suggest that the inhibition of 5-lipoxygenase metabolism may stimulate 15-lipoxygenase in human PMN.(ABSTRACT TRUNCATED AT 250 WORDS)

UI MeSH Term Description Entries
D007975 Leukotriene B4 The major metabolite in neutrophil polymorphonuclear leukocytes. It stimulates polymorphonuclear cell function (degranulation, formation of oxygen-centered free radicals, arachidonic acid release, and metabolism). (From Dictionary of Prostaglandins and Related Compounds, 1990) 5,12-HETE,5,12-diHETE,LTB4,Leukotriene B,Leukotriene B-4,Leukotrienes B,5,12 HETE,5,12 diHETE,B-4, Leukotriene,Leukotriene B 4
D009504 Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. LE Cells,Leukocytes, Polymorphonuclear,Polymorphonuclear Leukocytes,Polymorphonuclear Neutrophils,Neutrophil Band Cells,Band Cell, Neutrophil,Cell, LE,LE Cell,Leukocyte, Polymorphonuclear,Neutrophil,Neutrophil Band Cell,Neutrophil, Polymorphonuclear,Polymorphonuclear Leukocyte,Polymorphonuclear Neutrophil
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000838 Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Anion
D001091 Arachidonate Lipoxygenases Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates. These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids. The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . Arachidonic Acid Lipoxygenase,Lipoxygenase, Arachidonic Acid,Lipoxygenases, Arachidonate
D001241 Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. (From Martindale, The Extra Pharmacopoeia, 30th ed, p5) Acetylsalicylic Acid,2-(Acetyloxy)benzoic Acid,Acetysal,Acylpyrin,Aloxiprimum,Colfarit,Dispril,Easprin,Ecotrin,Endosprin,Magnecyl,Micristin,Polopirin,Polopiryna,Solprin,Solupsan,Zorprin,Acid, Acetylsalicylic
D013481 Superoxides Highly reactive compounds produced when oxygen is reduced by a single electron. In biological systems, they may be generated during the normal catalytic function of a number of enzymes and during the oxidation of hemoglobin to METHEMOGLOBIN. In living organisms, SUPEROXIDE DISMUTASE protects the cell from the deleterious effects of superoxides. Superoxide Radical,Superoxide,Superoxide Anion
D015936 Complement C5a The minor fragment formed when C5 convertase cleaves C5 into C5a and COMPLEMENT C5B. C5a is a 74-amino-acid glycopeptide with a carboxy-terminal ARGININE that is crucial for its spasmogenic activity. Of all the complement-derived anaphylatoxins, C5a is the most potent in mediating immediate hypersensitivity (HYPERSENSITIVITY, IMMEDIATE), smooth MUSCLE CONTRACTION; HISTAMINE RELEASE; and migration of LEUKOCYTES to site of INFLAMMATION. C5a Complement,Complement 5a,Complement Component 5a,C5a, Complement,Complement, C5a,Component 5a, Complement
D016227 Benzoquinones Benzene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. 1,2-Benzoquinones,1,4-Benzoquinones,Benzodiones,2,5-Cyclohexadiene-1,4-Diones,o-Benzoquinones,p-Benzoquinones
D016718 Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. (all-Z)-5,8,11,14-Eicosatetraenoic acid,Arachidonic Acid, (all-Z)-Isomer, 1-(14)C-Labeled,Arachidonic Acid, (all-Z)-isomer, 3H-Labeled,Arachidonic Acid, Ammonium Salt, (all-Z)-Isomer,Arachidonic Acid, Cerium Salt, (all-Z)-Isomer,Arachidonic Acid, Cesium Salt, (all-Z)-Isomer,Arachidonic Acid, Lithium Salt, (all-Z)-Isomer,Arachidonic Acid, Potassium Salt, (all-Z)-Isomer,Arachidonic Acid, Sodium Salt,Arachidonic Acid, Sodium Salt, (all-Z)-Isomer,Arachidonic Acid, Zinc Salt, (all-Z)-Isomer,Sodium Arachidonate,Vitamin F,Arachidonate, Sodium

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