Abstract
The effects of nordihydroguairetic acid (NDGA), 3-amino-1-trifluoromethyl-)-phenyl-2-pyrazoline (BW755c), eicostatetraynoic acid (ETYA), phenidone, quercetin, and indomethacin (INDO) on the synthesis of 15-hydroxyeicosatatetraenoic acid (15-HETE) from soybean 15-lipoxygenase, leukotriene B4 (LTB4 from 5-lipoxygenase, and prostaglandin E2 (PGE2 from cyclooxygenase enzymes of rat neutrophils and mouse peritoneal macrophages were investigated. All of the drugs caused a dose-related inhibition of increased oxygen consumption by soybean 15-lipoxygenase in the presence of arachidonic acid and the rank order of potency was phenidone ≥ BW755c > ETYA > quercetin > NDGA > indomethacin. The reduction in oxygen consumption correlated with a reduction of 15-HETE formation as identified by high-performance liquid chromatography. Apart from indomethacin, these drugs were also effective against the rat neutrophil 5-lipoxygenase, although the rank order of potency did not correlate with that obtained with soybean 15-lipoxygenase. Furthermore, in both A23187-activated rat neutrophils and zymosan-activated mouse peritoneal macrophages the synthesis of prostaglandins was inhibited by all of these drugs. In the neutrophils, the rank order of potency was INDO > ETYA > BW755c > quercetin > NDGA > phenidone, whereas in mouse peritoneal macrophages, the order was INDO > ETYA > BW755c > NDGA > quercetin > phenidone. These results suggest that putative lipoxygenase inhibitors exhibit both qualitative and quantitative differences in their effects on both lipoxygenases and cyclooxygenases.
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References
Lewis, R. A., andK. F. Austen. 1981. Mediation of local homeostasis and inflammation by leukotrienes and their mast cell-dependent compounds.Nature 293:103–108.
Samuelsson, B., S. Hammarstrom, R. C. Murphy, andP. Borgeat. 1980. Leukotrienes and slow reacting substances (SRS-A).Allergy 35:375–381.
Piper, P. J., M. N. Samhoun, J. R., Tippins, T. J. Williams, M. A. Palmer, andM. J. Peck. 1981. Pharmacological studies on pure SRS-A and synthetic leukotrienes C4 and D4. In SRS-A and Leukotrienes. P. J. Piper, editor. Research Studies Press, John Wiley, New York, 81–89.
Drazen, J. M., K. F. Austen, andR. A. Lewis. 1980. Comparative airway and vascular activities of leukotriene C-l and D in vivo and in vitro.Proc. Natl. Acad. Sci. U.S.A. 77:4354–4358.
Michelassi, F., L. Landa, R. D. Hill, E. Lowenstein, W. D. Watkins, A. J. Petkan, andH. M. Zapol. 1982. Leukotriene D4: A potent cocoronary artery vascoconstrictor associated with impaired ventricular contraction.Science 217:841–843.
Hanna, C. J., M. K. Bach, P. D. Pare, andR. R. Schellenberg. 1981. Slow-reacting substances (leukotrienes) contract human airway and pulmonary vascular smooth muscle in vitro.Nature 290:343–344.
Hedqvist, P., S. E. Dahlen, L. Gustafsson, S. Hammarstrom, andB. Samuelsson. 1980. Biological profile of leukotrienes C4 and D4.Acta Physiol. Scand. 110:331–333.
Holroyde, M. D., R. E. Altounyan, M. Cole, M. Dixon, andE. V. Elliott. 1981. Bronchoconstriction produced in man by leukotriene C and D.Lancet 2:17–18.
Dahlen, S. E., P. Hedqvist, S. Hammarstrom, andB. Samuelsson. 1980. Leukotrienes and potent constrictors of human bronchi.Nature 288:484–486.
Morom, Z., J. H. Shelhamer, M. K. Bach, D. R. Morton, andM. Kaliner. 1982. Slowreacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro.Am. Rev. Respir. Dis. 126:449–451.
Williams, T. J., andP. J. Piper. 1980. The action of chemically pure SRS-A on the microcirculation in vivo.Prostaglandins 19:779–789.
Dahlen, S. E., J. Bjork, P. Hedqvist, K. E. Arfors, S. Hammarstrom, J. A. Lindgren, andB. Samuelsson. 1981. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: In vivo effects with relevance to the acute inflammatory response.Proc. Natl. Acad. Sci. U.S.A. 78:3887–3891.
Ford-Hutchinson, A. W., M. A. Bray, M. V. Doig, M. E. Shipley, andM. J. H. Smith, 1980. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.Nature 286:264–265.
Goetzl, E. J., A. R. Brash, A. J. Tauber, J. A. Oates, andW. C. Hubbard, 1980. Modulation of human neutrophil function by monohydroxy-eicosatetraenoic acids.Immunology 39:491–501.
Stenson, W. F., andC. W. Parker, 1980. Monohydroxyeicosatetraenoic acids (HETEs) induce degranulation of human neutrophils.J. Immunol. 124:2100–2103.
Klickstein, L. B., Shapleigh, C., andGoetzl, E. J., 1980. Lipoxygenation of arachidonic acid as a source of polymorphonuclear leukocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondyloarthritis.J. Clin. Invest. 66:1166–1170.
Yen, S. S., andH. G. Morris, 1981. An imbalance in arachidonic acid metabolism in asthma.Biochem. Biophys. Res. Commun. 103:774–779.
Hamberg, M., 1976. On the formation of thromboxane B2 and 12L-hydroxy-5, 8, 10, 14-eicostetraenoic acid (12–20:4) in tissues from the guinea pig.Biochim. Biophys. Acta 431:651–654.
Armour, C. L., J. M. Hughes, J. P. Seale, andD. M. Temple, 1981. Effect of lipoxygenase inhibitors on release of slow-reacting substances from human lung.Eur. J. Pharmacol. 72:93–96.
Harvey, J., andD. J. Osborne. 1983. A rapid method for detecting inhibitors of both cyclooxygenase and lipoxygenase metabolites of arachidonic acid.J. Pharmacol. Methods 9:147–155.
Higgs, G. A., R. J. Flower, andJ. R. Vane. 1979. A new approach to antiinflammatory drugs.Biochem. Pharmacol. 28:1959–1961.
Radmark, O., C. Malmsten, andB. Samuelsson. 1980. The inhibitory effects BW755c on arachidonic acid metabolism in human polymorphonuclear leukocytes.FEBS Lett. 110:213–215.
Hamberg, M., andB. Samuelsson. 1974. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets.Proc. Natl. Acad. Sci. U.S.A. 71:3400–3404.
Blackwell, G. J., andR. J. Flower. 1978. 1-Phenyl-3-pyrazolidone: An inhibitor of cyclicoxygenase and lipoxygenase pathways in lung and platelets.Prostaglandins 16:417–425.
Hope, W. C., A. F. Welton, C. F. Nagy, C. B. Bernardo, andJ. W. Coffey. 1983. In vitro inhibition of the biosynthesis of slow reacting substance of anaphylaxis (SRS-A) and lipoxygenase activity by quercetin.Biochem. Pharmacol. 32:367–371.
Baumann, J., F. V. Bruchhausan, andG. Wurm. 1980. Flavanoids and related compounds as inhibitors of arachidonic acid peroxidation.Prostaglandins 20:727–739.
Robak, J., andZ. Dumec. 1982. The influence and some 3-amino-2-pyrazoline derivatives on cyclooxygenase and lipoxidase activities.Biochem. Pharmacol. 31:1955–1959.
Knippel, I., J. Baumann, F. Bruchhausen, andG. Wurm. 1981. Interactions of sulfhydryl agents and soybean lipoxygenase inhibitors.Biochem. Pharmacol. 30:1677–1684.
Flower, R. J. 1974. Drugs which inhibit prostaglandin biosynthesis.Pharmacol. Rev. 26:33–66.
Vanderhoek, J. Y., R. W. Bryant, andJ. M. Bailey. 1980. Inhibition of leukotriene biosynthesis by the leukocyte product, 15-hydroxy-5, 8, 11, 13-eicosatetraenoic acid.J. Biol. Chem. 255:10064–10066.
Lanni, C., andE. L. Becker. 1983. Inhibition of neutrophil phospholipase A2 (PLA2 by bromophenylaculbromide (BPB), nordihydroguiaretic acid (NDGA), eicosatetraenoic acid (ETYA) and quercetin.Fed. Proc. 42:1906.
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Chang, J., Skowronek, M.D., Cherney, M.L. et al. Differential effects of putative lipoxygenase inhibitors on arachidonic acid metabolism in cell-free and intact cell preparations. Inflammation 8, 143–155 (1984). https://doi.org/10.1007/BF00916090
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DOI: https://doi.org/10.1007/BF00916090