Eicosanoids pp 45-59 | Cite as

Metabolism of Eicosanoids in Mammalian Cells

  • Robert C. Murphy
Part of the NATO ASI Series book series (NSSA, volume 283)


Eicosanoid lipid mediators (prostaglandins, thromboxanes, and leukotrienes) play an important role in mammalian biochemistry serving as chemical substances of intracellular communication and cellular activation. Discoveries of their biological activities and roles in normal physiology and pathophysiology are legion. An important question to consider with such biologically active compounds is how activity is terminated. For eicosanoids, metabolism is the primary mechanism by which these substances are removed from tissues and ultimately the body. Therefore, a central facet in studying the biochemistry of lipid mediators has been investigations into the means by which eicosanoids are metabolically converted into other compounds and subsequently eliminated.


Urinary Metabolite Entry Rate COOH COOH Human Polymorphonuclear Leukocyte Unique Metabolite 
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  1. 1.
    Granstrom, E. Two-dimensional thin-layer chromatography of prostaglandins and related compounds. Methods of Enzymology, 86:485–504, 1982.Google Scholar
  2. 2.
    Diczfalusy, U. β-Oxidation of eicosanoids. Prog. Lipid Res. 33:403–438, 1994.PubMedCrossRefGoogle Scholar
  3. 3.
    Hansen, H. S. 15-Hydroxy prostaglandin dehydrogenase: A Review. Prostaglandins 12:647–679, 1976.PubMedGoogle Scholar
  4. 4.
    Xun, C.Q., Ensor, C.M., and Tai, H.H. Regulation of synthesis and activity of NAD+-dependent 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) by dexamethasone and phorbol ester in human erythroleukemia (HEL) cells. Biochem. Biophys. Res. Commun. 177:1258–1265 (1991).PubMedCrossRefGoogle Scholar
  5. 5.
    Watanabe, T., Shimizu, T., Narumiya, S., and Hayaishi, O. NADP-linked 15-hydroxyprostaglandin dehydrogenase for prostaglandin D in human blood platelets. Arch. Biochem. Biophys. 216:372–379 (1982).PubMedCrossRefGoogle Scholar
  6. 6.
    Hansen, H.S. Purification and characterization of a 15-keto prostaglandin delta 13-reductase from bovine lung. Biochim. Biophys. Acta 547:136–145 (1979).Google Scholar
  7. 7.
    Watanabe, T., Shimizu, T., Iguchi, S., Wakatsuka, H., Hayashi, M., and Hayaishi, O. An NADP-linked prostaglandin D dehydrogenase in swine brain. J. Biol. Chem. 250:548–552 (1975).Google Scholar
  8. 8.
    Levasseur, S., Friedman, Y., and Burke, G. Prostaglandin metabolism in the rat adrenal cortex: Characterization of prostaglandin-9-ketoreductase and 15-hydroxyprostaglandin dehydrogenase. Biochem. Biophys. Res. Commun. 95:236–242 (1980).PubMedCrossRefGoogle Scholar
  9. 9.
    Diczfalusy, U., Alexson, S.E.H., and Petersen, J.I. Chain-shortening of prostaglandin F2a by rat liver peroxisomes. Biochem. Biophys. Res. Commun. 144:1206–1213 (1987).PubMedCrossRefGoogle Scholar
  10. 10.
    Reddy, J.K. and Mannaerts, G.P. Peroxisomal lipid metabolism. Annu. Rev. Nutr. 14:343–370 (1994).PubMedCrossRefGoogle Scholar
  11. 11.
    Schulz, H. Beta oxidation of fatty acids. Biochim. Biophys. Acta 1081:109–120 (1991).PubMedCrossRefGoogle Scholar
  12. 12.
    Aoyama, T., Hardwick, J.P., Imaoka, S., Funae, Y., Gelboin, H.V., and Gonzalez, F.J. Clofibrate-inducible rat hepatic P450s IVA1 and IVA3 catalyze the ω-and (ω-l)-hydroxylation of fatty acids and the ω-hydroxylation of prostaglandins E1 and F2a. J. Lipid Res. 31:1477–1482 (1990).PubMedGoogle Scholar
  13. 13.
    Roberts, L.J., Sweetman, B.J., Payne, N.A., and Oates, J.A. Metabolism of thromboxane B2 in man. Identification of the major urinary metabolite. J. Biol. Chem. 252:7415–7417 (1977).PubMedGoogle Scholar
  14. 14.
    Patrono, C., Ciabattoni, G., Pugliese, F., Pierucci, A., Blair, I.A., and FitzGerald, G.A. Estimated rate of thromboxane secretion into the circulation of normal humans. J. Clin. Invest. 77:590–594 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    Granstrom, E., Westlund, P., Kumiin, M., and Nordenstrom, A. Monitoring thromboxane production in vivo: metabolic and analytical aspects. Adv. Prostaglandin. Thromboxane. Leukot. Res. 15:67–70 (1985).PubMedGoogle Scholar
  16. 16.
    Catella, F., Healy, D., Lawson, J.A., and FitzGerald, G.A. 11-Dehydrothromboxane B2: A quantitative index of thromboxane A2 formation in the human circulation. Proc. Natl. Acad. Sci. U. S.A. 83:5861–5865 (1986).PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenkranz, B., Fischer, C., Reimann, I., Weimer, K.E., Beck, G., and Frolich, J.C. Identification of the major metabolite of prostacyclin and 6-ketoprostaglandin F1a in man. Biochim. Biophys. Acta 619:207–213 (1980).PubMedCrossRefGoogle Scholar
  18. 18.
    FitzGerald, G.A., Brash, A.R., Falardeau, P., and Oates, J.A. Estimated rate of prostacyclin secretion into the circulation of normal man. J. Clin. Invest. 68:1272–1275 (1981).PubMedCrossRefGoogle Scholar
  19. 19.
    Samuelsson, B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220:568–575 (1983).PubMedCrossRefGoogle Scholar
  20. 20.
    Nagaoka, I., Yamada, M., Kira, S., and Yamashita, T. Comparative studies on the leukotriene D4-metabolizing enzyme of different types of leukocytes. Comp. Biochem. Physiol. 89B:375–380 (1988).Google Scholar
  21. 21.
    Leier, I., Muller, M., Jedlitschky, G., and Keppler, D. Leukotriene uptake by hepatocytes and hepatoma cells. Eur. J. Biochem. 209:281–289 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    Ishikawa, T., Muller, M., Klunemann, C., Schaub, T., and Keppler, D. ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. Role of the ATP-dependent transport system for glutathione S-conjugates. J. Biol. Chem. 265:19279–19286 (1990).PubMedGoogle Scholar
  23. 23.
    Leier, I., Jedlitschky, G., Buchholz, U., Cole, S.P., Deeley, R.G., and Keppler, D. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J. Biol. Chem. 269:27807–27810 (1994).PubMedGoogle Scholar
  24. 24.
    Uehara, N., Ormstad, K., Orning, L., and Hammarstrom, S. Characteristics of the uptake of cysteine-containing leukotrienes by isolated hepatocytes. Biochim. Biophys. Acta 732:69–74 (1983).PubMedCrossRefGoogle Scholar
  25. 25.
    Stene, D.O. and Murphy, R.C. Metabolism of leukotriene E4 in isolated rat hepatocytes: Identification of beta-oxidation products of sulfidopeptide leukotrienes. J. Biol. Chem. 263:2773–2778 (1988).PubMedGoogle Scholar
  26. 26.
    Sala, A., Voelkel, N., Maclouf, J., and Murphy, R.C. Leukotriene E4 elimination and metabolism in normal human subjects. J. Biol. Chem. 265:21771–21778 (1990).PubMedGoogle Scholar
  27. 27.
    Jedlitschky, G., Huber, M., Volkl, A., Muller, M., Leier, I., Muller, J., Lehmann, W.D., Fahimi, H.D., and Keppler, D. Peroxisomal degradation of leukotrienes by β-oxidation from the _-end. J. Biol. Chem. 266:24763–24772 (1991).PubMedGoogle Scholar
  28. 28.
    Maclouf, J., Antoine, C., De Caterina R., Sicari, R., Murphy, R.C., Patrignani, P., Loizzo, S., and Patrono, C.: Entry rate of leukotriene C4 into the vascular compartment and subsequent metabolism in healthy subjects. Am. J. Physiol. 263:H244–H249 (1992).PubMedGoogle Scholar
  29. 29.
    Hansson, G., Lindgren, J.A., Dahlen, S.E., Hedqvist, P., and Samuelsson, B. Identification and biological activity of novel ω-oxidized metabolites of leukotriene B4 from human leukocytes. FEBS Lett. 130:107–112 (1981).PubMedCrossRefGoogle Scholar
  30. 30.
    Soberman, R.J., Okita, R.T., Fitzsimmons, B., Rokach, J., Spur, B., and Austen, K.F. Stereochemical requirements for substrate specificity of LTB4 20-hydroxylase. J. Biol. Chem. 262:12421–12427 (1987).PubMedGoogle Scholar
  31. 31.
    Romano, M.C., Eckardt, R.D., Bender, P.E., Leonard, T.B., Straub, K.M., and Newton, J.F. Biochemical characterization of hepatic microsomal leukotriene B4 hydroxylases. J. Biol. Chem. 262:1590–1595 (1987).PubMedGoogle Scholar
  32. 32.
    Shak, S. and Goldstein, I.M.-Oxidation is the major pathway for the catabolism of leukotriene B4 in human polymorphonuclear leukocytes. J. Biol. Chem. 259:10181–10187 (1984).PubMedGoogle Scholar
  33. 33.
    Soberman, R.J., Sutyak, J.P., Okita, R.T., Wendelborn, D.F., Roberts, L.J., and Austen, K.F. The identification and formation of 20-aldehyde leukotriene B4. J. Biol. Chem. 263:7996–8002 (1988).PubMedGoogle Scholar
  34. 34.
    Sumimoto, H. and Minakami, S. Oxidation of 20-hydroxyleukotriene B4 to 20-carboxyleukotriene B4 by human neutrophil microsomes. Role of aldehyde dehydrogenase and leukotriene B4 ω-hydroxylase (cytochrome P-450LTBω) in leukotriene B4 ω-oxidation. J. Biol. Chem. 265:4348–4353 (1990).PubMedGoogle Scholar
  35. 35.
    Kikuta, Y., Kusunose, E., Kondo, T., Yamamoto, S., Kinoshita, H., and Kusunose, M. Cloning and expression of a novel form of leukotriene B4 ω-hydroxylase from human liver. FEBS Lett. 348:70–74 (1994).PubMedCrossRefGoogle Scholar
  36. 36.
    Baumert, T., Huber, M., Mayer, D., and Keppler, D. Ethanol-induced inhibition of leukotriene degradation by β-Oxidation. Eur. J. Biochem. 182:223–229 (1989).PubMedCrossRefGoogle Scholar
  37. 37.
    Shirley, M.A. and Murphy, R.C. Novel 3-hydroxylated leukotriene B4 metabolites from ethanol-treated rat hepatocytes. J. Am. Soc. Mass Spectrom. 3:762–768 (1992).CrossRefGoogle Scholar
  38. 38.
    Wheelan, P., Sala, A., Folco, G., Nicosia, S., Falck, J.R., Bhatt, R.K., and Murphy, R.C. Stereochemical analysis and biological activity of 3-hydroxy-leukotriene B4: A metabolite from ethanol treated rat hepatocytes. J. Pharmacol. Exp. Ther. 271:1514–1519 (1994).PubMedGoogle Scholar
  39. 39.
    Shirley, M.A. and Murphy, R.C. Metabolism of leukotriene B4 in isolated rat hepatocytes: Involvement of 2,4-dieneoyl CoA reductase in leukotriene B4 metabolism. J. Biol. Chem. 265:16288–16295 (1990).PubMedGoogle Scholar
  40. 40.
    Yokomizo, T., Izumi, T., Takahashi, T., Kasama, T., Kobayashi, Y., Sato, F., Taketani, Y., and Shimizu, T. Enzymatic inactivation of leukotriene B4 by a novel enzyme found in the porcine kidney. Purification and properties of leukotriene B4 12-hydroxydehydrogenase. J. Biol. Chem. 268:18128–18135 (1993).PubMedGoogle Scholar
  41. 41.
    Wheelan, P., Zirrolli, J.A., Morelli, J.G., and Murphy, R.C. Metabolism of leukotriene B4 by cultured human keratinocytes: Formation of glutathione conjugates and dihydro metabolites. J. Biol. Chem. 268:25439–25448 (1993).PubMedGoogle Scholar
  42. 42.
    Powell, W.S. and Gravelle, F. Metabolism of 6-trans isomers of leukotriene B4 to dihydro products by human polymorphonuclear leukocytes. J. Biol. Chem. 263:2170–2177 (1988).PubMedGoogle Scholar
  43. 43.
    Wheelan, P. and Murphy, R.C.: Metabolism of 6-trans isomers of leukotriene B4 in cultured hepatoma cells and in human polymorphonuclear leukocytes: Identification of a Δ6-reductase metabolic pathway. J. Biol. Chem., in press.Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Robert C. Murphy
    • 1
  1. 1.National Jewish Center for Immunology and Respiratory MedicineDenverUSA

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