Metabolism of Sulfidopeptide Leukotrienes

  • Danny O. Stene
  • Robert C. Murphy
Conference paper
Part of the NATO ASI Series book series (NSSA, volume 177)


Until recently there has been very little known about the ultimate metabolitc fate of the sulfidopeptide leukotrienes. A basic principle of the pharmacology of mediator substances requires that mechanisms exist for biological inactivation of these very potent molecules. One such mechanism might be simple uptake of leukotrienes by the cells which make or respond to them. Studies showing that LTC4, produced in the isolated perfused lung in response to the calcium ionophore A23187, was largely retained by the lung over a span of 10 minutes, and that very little conversion to LTD4/LTE4 took place, suggesting the possibility that a reuptake mechanism for LTC4 in the lung existed (1). Other eicosanoids (LTB4, 6-keto-PGF1, thromboxane B2 and PGE2) were largely released into the perfusate. It is also possible that LTC4 was retained through binding to tissue proteins with high affinity and not taken up into cells. Since direct experiments have now shown that leukotrienes are not stored in cells from which they are released, and, while the retention of LTC4 by the isolated perfused rat lung has not been fully explained, simple reuptake of LTC4 in the lung seems unlikely. At present it is thought that metabolic biotransformation is the primary mechanism of inactivation of the leukotrienes.


Enterohepatic Circulation Polar Metabolite Calcium Ionophore A23187 Intraduodenal Administration Metabolic Biotransformation 
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  1. 1.
    J.Y. Westcott, T.J. McDonnell, P. Bostwick, and N.F. Voelkel, Eicosanoid production in isolated perfused lungs stimulated with calcium ionophore A23187. Am. Rev. Respir. Dis.,in press.Google Scholar
  2. 2.
    R.K. Root, J. Metcalf, N. Oshino, and B. Chance, 1975, H202 release from human granulocytes during phagocytosis I. Documentation, quantitation, and some regulating factors. J. Clin. Invest., 55: 945.PubMedCrossRefGoogle Scholar
  3. 3.
    R.A. Clark and S. Szot, 1982, Chemotactic factor inactivation by stimulated human eosinophils mediated by myeloperoxidase-catalyzed methionine oxidation. J. Immunol., 128: 1507.PubMedGoogle Scholar
  4. 4.
    C.W. Lee, R.A. Lewis, E.J. Corey, A. Barton, H. Oh, A.I. Tauber, K.F. Austen, 1982, Oxidative inactivation of leukotriene C4 by stimulated human polymorphonuclear leukocytes. Proc. Natl. Acad. Sci. USA, 79: 4166.PubMedCrossRefGoogle Scholar
  5. 5.
    E.J. Goetzl, 1982, The conversion of leukotriene C4 to isomers of leukotriene B4 by human eosinophil peroxidase. Biochem. Biophys. Res. Commun., 106:2’70.Google Scholar
  6. 6.
    W.R. Henderson and S.J. Klebanoff, 1983, Leukotriene B4, C4, D4, and E4 inactivation by hydroxyl radicals. Biochem. Biophys. Res. Commun., 110: 266.PubMedCrossRefGoogle Scholar
  7. 7.
    M.A. Veill, W.R. Henderson, and S.J. Klebanoff, 1985, Oxidative degredation of leukotriene C4 by human monocytes and monocyte-derived macrophage. J. Exp. Med., 162: 1634.CrossRefGoogle Scholar
  8. 8.
    T.W. Harper, J.Y. Westcott, N.F. Voelkel, and R.C. Murphy, 1984, Metabolism of LTB4 and LTC4 in the isolated perfused rat lung. J. Biol. Chem., 259: 14437.PubMedGoogle Scholar
  9. 9.
    G. Hansson, J.A. Lindgren, S.E. Dahlen, P. Hedqvist, and B. Samuelsson, 1981, Identification and biological activity of novel w -oxidized metabolites of leukotriene B4 from human leukocytes. FEBS Lett., 130: 107.PubMedCrossRefGoogle Scholar
  10. 10.
    S.J., Feinmark, J.A. Lindgren, H.E. Claesson, C. Malmsten, B. Samuelsson, 1981, Stimulation of human leukocyte degranulation by leukotriene B4 and its w-oxidized metabolites. FEBS Lett., 136: 141.CrossRefGoogle Scholar
  11. 11.
    T.W. Harper, M.J. Garrity, and R.C. Murphy, 1986, Metabolism of leukotriene B4 in isolated rat hepatocytes. Identification of a novel 18-carboxy-dinorLTB4 metabolite. J. Biol. Chem., 261: 5414.PubMedGoogle Scholar
  12. 12.
    M.C. Ramano, R.D. Eckardt, P.E. Bender, T.B. Leonard, K.M. Straub, and J.F. Newton, 1987, Biochemical characterization of hepatic microsomal leukotriene B4 hydroxylases. J. Biol. Chem., 262: 1590.Google Scholar
  13. 13.
    R.J. Soberman, J.P. Sutyak, R.T. Okita, D.F. Wendelbgrn, L.J. Roberts, and K.F. Austen, 1988, The identification and formation of 20-aldehyde leukotriene B4. J. Biol. Chem., 263: 7996.PubMedGoogle Scholar
  14. 14.
    W.E. Serafin, J.A. Oates, W.C. Hubbard, 1984, Metabolism of leukotriene B4 in the monkey. Identification of the principal nonvolatile metabolite in urine. Prostaglandins, 27: 899.PubMedCrossRefGoogle Scholar
  15. 15.
    L.-E. Appelgren and S. Hammarstrom, 1982, Distribution and metabolism of 3H-labeled leukotriene C3 in the mouse. J. Biol. Chem., 257: 531.PubMedGoogle Scholar
  16. 16.
    K. Ormstad, N. Uehara, S. Orrenius, L. Orning, and S. Hammarstrom, 1982, Uptake and metabolism of leukotriene C3 by isolated rat organs and cells. Biochem. Biophys. REs. Commun. 104: 1434.PubMedCrossRefGoogle Scholar
  17. 17.
    N. Uehara, K. Ormstad, L. Orning, and S. Hammarstrom, 1983, Characteristics of the uptake of cysteine-containing leukotrienes by isolated hepatocytes. Biochem. Biophys. Acta, 732: 69.PubMedCrossRefGoogle Scholar
  18. 18.
    G. Weckbecker and D.O.R. Keppler, 1986, Leukotriene C4 metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes. Eur. J. Biochem., 154: 559.PubMedCrossRefGoogle Scholar
  19. 19.
    L. Orning, E. Norin, B. Gustafsson, and S. Hammarstrom, 1986, In vivo metabolism of leukotriene C4 in germ-free and conventional rats. J. Biol.Chem.,261:766.PubMedGoogle Scholar
  20. 20.
    W. Hagmann, C. Denzlinger, S. Rapp, G. Weckbecker, and D. Keppler, 1986, Identification of the major engoenous leukotriene metabolite in the bile of rats as N-acetyl leukotriene E4. Prostaglandins, 31: 239.PubMedCrossRefGoogle Scholar
  21. 21.
    M. Huber and D. Keppler, 1987, Inhibition of leukotriene D4 catabolism by Dpenicillamine. Eur. J. Biochem., 167: 73.PubMedCrossRefGoogle Scholar
  22. 22.
    R.C. Murphy, R. Mathews, and W. Pickett, W., Leukotrienes and thromboxanes: Metabolites of essential fatty acids with significant untoward pharmacological properties, in: “Nutritional Factors: Modulating Effects of Metabolic Processes,” E.G. Bassett, ed., Raven Press, N.Y. (1981).Google Scholar
  23. 23.
    M. Soderstrom, S. Hammarstrom, and B. Mannervick, 1988, Leukotriene C synthase in mouse mastocytoma cells. An enzyme distinct from cytosolic and microsomal glutathione transferases. Biochem. J., 250: 713.PubMedGoogle Scholar
  24. 24.
    J. Caldwell, Conjugation reactions of nitrogen centers, in: “Metabolic Basis of Detoxication,” W.B. Jakoby, J.R. Bend, and J. Caldwell, eds., Academic Press, New York (1982).Google Scholar
  25. 25.
    K. Bernstrom and S. Hammarstrom, 1986, Metabolism of leukotriene E4 by rat tissues: Formation of N-acetyl leukotriene E4. Arch. Biochem. Biophys., 244: 486.PubMedCrossRefGoogle Scholar
  26. 26.
    C. Denzlinger, A. Guhlmann, W. Hagmann, P.H. Scheuber, F. Scheyer, D. Wilker, D.K. Hammer, and D. Keppler, 1986, Cysteinyl leukotrienes undergo enterohepatic circulation. Prostag. Leukotr. Med., 21: 321.CrossRefGoogle Scholar
  27. 27.
    M. Humber, A. Guhlmann, P.L.M. Jansen, and D. Keppler, 1987, Hereditory defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion. Hepalology, 7: 224.CrossRefGoogle Scholar
  28. 28.
    J.Y. Westcott, T.J. McDonnel, and N.F. Voelkel, 1988, Alveolar transfer and metabolism of eicosaniods in the ratGoogle Scholar
  29. 29.
    C. Denzlinger, A. Guhlmann, P.H Keppler, 1986, Metabolism and monkey. J. Biol. Chem., 261: 15601.PubMedGoogle Scholar
  30. 30.
    L. Orning, L. Kaijser, and S. leukotriene C4 in maw Urinary Res. Commun.,130:214.Google Scholar
  31. 31.
    S.R. Wagle and W.R. Ingebretsen, Isolation, purification, and metabolic characteristics of rat liver hepatocytes, in: “Methods in Enzymology,” J.M. Lowenstein, ed., Academic Press, New York (1975).Google Scholar
  32. 32.
    D.O. Stene and R.C. Murphy, 1988, Metabolism of leukotriene E4 in isolated rat hepatocytes: Identification of beta-oxidation products of sulfidopeptide leukotrienes. J. Biol. Chem. 263: 2773.PubMedGoogle Scholar
  33. 33.
    R.C. Murphy and D.O. Stene, 1988, Oxidative metabolism of leukotriene E4 by rat hepatocytes. Ann. NY Acad. Sci., 524: 35.PubMedCrossRefGoogle Scholar
  34. 34.
    H.P. Koch, 1949, Absorption spectra and structure of organic sulfur compounds. Part I. Unsaturated sulphides. J. Chem. Soc., 387.Google Scholar
  35. 35.
    W.-H. Kunau and P. Dommes, 1978, Degradation of unsaturated fatty acids. Identification of intemediates in the degradation of cis-4-decenoyl-CoA by extracts of beff liver mitochondria. Eur. J. Biochem., 91: 533.PubMedCrossRefGoogle Scholar
  36. 36.
    C.-H. Chu, L. Kushner, D. Cuebas, and H. Schulz, 1984, The activity of 3hydroxyacyl-CoA epemerase is insufficient to account for the rate of linoleate oxidation in rat heart mitochondria. Evidence for a modified pathway of linoleate degradation. Biochem. Biophys. Res. Commun., 118: 162.PubMedCrossRefGoogle Scholar
  37. 37.
    J.A. Zirrolli, A. Fradin, J. Maclouf, and R.C. Murphy, 1988, Analysis of LTB4 and 20-hydroxy-LTB4 in whole blood challenged with zymosan. Proc. Ann. Conf. Mass Spectrom. 36:, in press.Google Scholar
  38. 38.
    V. Diczfalusy, S.E.H. Alerson, and J.I. Pedersen, 1987, Chain-shortening of prostaglandin F2a by rat liver peroxisomes. Biochem. Biophys. Res. Commun., 144: 1206.PubMedCrossRefGoogle Scholar
  39. 39.
    P. Perrin, J. Zirrolli, D. Stene, J.P. Lellouche, J.P. Beaucourt, and R.C. Murphy, In vivo formation of fl-oxidized metabolites of leukotriene E4 in the rat. Prostaglandins,submitted.Google Scholar
  40. 40.
    H.A. Ball and D. Keppler, 1987, u-oxidation products of leukotriene E4 in bile and urine of the monkey. Biochem. Biophys. Res. Commun., 148: 664.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Danny O. Stene
    • 1
  • Robert C. Murphy
    • 1
  1. 1.Department of PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA

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