Skip to main content
SpringerLink
Log in
Book cover

Novel Inhibitors of Leukotrienes pp 63–82Cite as

Birkhäuser

Metabolism of leukotrienes and formation of new leukotriene structures

  • Chapter

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

The metabolism of leukotrienes is central to their effective operation as lipid mediators. Covalent modification of leukotriene structures results largely in reduced or terminated biological activity, thus making metabolism a major process limiting leukotriene action in vivo. The majority of the enzymatic pathways involved in metabolic processing are common to a host of other endogenous biochemical substances, in particular eicosanoids such as prostaglandins and thromboxanes. However, there are several enzymes rather specific for certain leukotrienes, suggesting a more unique role for such metabolic events mediated by these enzymes.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Lam BK, Gagnon L, Austen KF, Soberman RJ (1990) The mechanims of leukotriene B4 export from human polymorphonuclear leukocytes. J Biol Chem 265: 13438–13441

    PubMed  CAS  Google Scholar 

  2. Marleau S, Dallaire N, Poubelle PE, Borgeat P (1994) Metabolic disposition of leukotriene B4 (LTB4) and oxidation-resistant analogues of LTB4 in conscious rabbits. Br J Pharmacol 112: 654–658

    Article  PubMed  CAS  Google Scholar 

  3. Leier I, Muller M, Jedlitschky G, Keppler D (1992) Leukotriene uptake by hepatocytes and hepatoma cells. Eur J Biochem 209: 281–289

    Article  PubMed  CAS  Google Scholar 

  4. Lindgren JA, Hansson G, Samuelsson B (1981) Formation of novel hydroxylated eicosatetraenoic acids in preparations of human polymorphonuclear leukocytes. FEBS Lett 128: 329–335

    Article  PubMed  CAS  Google Scholar 

  5. Shak S, Goldstein IM (1985) Leukotriene B4 ω-hydroxylase in human polymorphonu-clear leukocytes: Partial purification and identification as a cytochrome P450. J Clin Invest 76: 1218–1228

    Article  PubMed  CAS  Google Scholar 

  6. Harper TW, Garrity MJ, Murphy RC (1986) Metabolism of leukotriene B4 in isolated rat hepatocytes. Identification of a novel 18-carboxy-19,20-dinor leukotriene B4 metabolite. J Biol Chem 261: 5414–5418

    PubMed  CAS  Google Scholar 

  7. Newton JF, Eckardt R, Bender PE, Leonard T, Straub K (1985) Metabolism of leukotriene B4 in hepatic microsomes. Biochem Biophys Res Commun 128: 733–738

    Article  PubMed  CAS  Google Scholar 

  8. Hansson G, Lindgren JA, Dahlen SE, Hedqvist P, Samuelsson B (1981) Identification and biological activity of novel omega-oxidized metabolites of leukotriene B4 from human leukocytes. FEBS Lett 130: 107–112

    Article  PubMed  CAS  Google Scholar 

  9. Clancy RM, Dahinden CA, Hugli TE (1984) Oxidation of leukotrienes at the co end: Demonstration of a receptor for the 20-hydroxy derivative of leukotriene B4 on human neutrophils and implications for the analysis of leukotriene receptors. Proc Natl Acad Sci USA 81: 5729–5733

    Article  PubMed  CAS  Google Scholar 

  10. Okita JR, Castle PJ, Okita RT (1993) Characterization of cytochromes P450 in liver and kidney of rats treated with di-(2-ethylhexyl)phthalate. J Biochem Toxicol 8: 135–144

    Article  PubMed  CAS  Google Scholar 

  11. Kikuta Y, Kusunose E, Endo K, Yamamoto S, Sogawa K, Fujii-Kuriyama Y, Kusunose M (1993) A novel form of cytochrome P-450 family in human polymorphonuclear leukocytes: cDNA cloning and expression of leukotriene B4 omega-hydroxylase. J Biol Chem 268: 9376–9380

    PubMed  CAS  Google Scholar 

  12. Chen L, Hardwick JP (1993) Identification of a new P450 subfamily, CYP4F1, expressed in rat hepatic tumors. Arch Biochem Biophys 300: 18–23

    Article  PubMed  CAS  Google Scholar 

  13. Kawashima H, Kusunose E, Thompson CM, Strobel HW (1997) Protein expression, characterization, and regulation of CYP4F4 and CYP4F5 cloned from rat brain. Arch Biochem Biophys 347: 148–154

    Article  PubMed  CAS  Google Scholar 

  14. Kikuta Y, Kusunose E, Kondo T, Yamamoto S, Kinoshita H, Kusunose M (1994) Cloning and expression of a novel form of leukotriene B4 omega-hydroxylase from human liver. FEBS Lett 348: 70–74

    Article  PubMed  CAS  Google Scholar 

  15. Soberman RJ, Sutyak JP, Okita RT, Wendelborn DF, Roberts LJ, Austen KF (1988) The identification and formation of 20-aldehyde leukotriene B4. J Biol Chem 263: 7996–8002

    PubMed  CAS  Google Scholar 

  16. Schluter B, Schonfeld W, Konig W (1988) Generation and metabolism of leukotrienes and release of histamine from human dispersed tonsillar cells. Scand J Immunol 27: 451–459

    Article  PubMed  CAS  Google Scholar 

  17. Schonfeld W, Schluter R, Hilger R, Konig (1988) Leukotriene generation and metabolism in isolated human lung macrophages. Immunol 65: 529–536

    CAS  Google Scholar 

  18. Gotoh Y, Sumimoto H, Takeshige K, Minakami S, Keppler D (1988) NADtdependent oxidation of 20-hydroxyleukotriene B4 to 20-carboxyleukotriene B4 by rat liver cytosol. Biochim Biophys Acta 960: 342–350

    Article  PubMed  CAS  Google Scholar 

  19. Baumert T, Huber M, Mayer D, Keppler D (1989) Ethanol-induced inhibition of leukotriene degradation by omega-oxidation. Eur J Biochem 182: 223–229

    Article  PubMed  CAS  Google Scholar 

  20. Shirley MA, Murphy RC (1992) Novel 3-hydroxylated leukotriene B4 metabolites from ethanol-treated rat hepatocytes. J Am Soc Mass Spectrom 3: 762–768

    Article  CAS  Google Scholar 

  21. Sumimoto H, Minakami S (1990) Oxidation of 20-hydroxyleukotriene B4 to 20-carboxyleukotriene B4 by human neutrophil microsomes. Role of aldehyde dehydrogenase and leukotriene B4 w-hydroxylase (cytochrome P-450LTBω) in leukotriene B4 cu-oxidation. J Biol Chem 265: 4348–4353

    PubMed  CAS  Google Scholar 

  22. Hankin JA, Clay CE, Murphy RC (1998): The effects of ethanol and acetaldehyde on the metabolism of prostaglandin E2 and leukotriene B4 in isolated rat hepatocytes. J Pharmacol Exp Ther 285: 155–161

    PubMed  CAS  Google Scholar 

  23. Powell WS (1987) Conversion of leukotriene B4 to dihydro and 19-hydroxy metabolites by rat polymorphonuclear leukocytes. Biochem Biophys Res Commun 145: 991–998

    Article  PubMed  CAS  Google Scholar 

  24. Powell WS, Gravelle F (1989) Metabolism of leukotriene B4 to dihydro and dihydro-oxo products by porcine leukocytes. J Biol Chem 264: 5364–5369

    PubMed  CAS  Google Scholar 

  25. Wainwright SL, Powell WS (1991) Mechanism for the formation of dihydro metabolites of 12-hydroxyeicosanoids: Conversion of leukotriene B4 and 12-hydroxy-5,8,10,14eicosatetraenoic acid to 12-oxo intermediates. J Biol Chem 266: 20899–20906

    PubMed  CAS  Google Scholar 

  26. Yokomizo T, Izumi T, Takahashi T, Kasama T, Kobayashi Y, Sato F, Taketani Y, Shimizu T (1993) 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

    PubMed  CAS  Google Scholar 

  27. Powell WS, Rokach J, Khanapure SP, Manna S, Hashefi M, Gravel S, MacLeod RJ, Falck JR, Bhatt RK (1996) Effects of metabolites of leukotriene B4 on human neutrophil migration and cytosolic calcium levels. J Pharm Exp Ther 276: 728–236

    CAS  Google Scholar 

  28. Kaever V, Damerau B, Wessel K, Resch K (1988) Biological properties of dihydro-leukotriene B4, an alternative leukotriene B4 metabolite. FEBS Lett 231: 385–388

    Article  PubMed  CAS  Google Scholar 

  29. Yokomizo T, Ogawa Y, Uozumi N, Kume K, Izumi T, Shimizu T (1996) cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase. J Biol Chem 271: 2844–2850

    Article  PubMed  CAS  Google Scholar 

  30. Ensor CM, Zhang H, Tai HH (1998) Purification, cDNA cloning and expression of 15-oxoprostaglandin 13-reductase from pig lung. Biochem J 330: 103–108

    PubMed  CAS  Google Scholar 

  31. Romano MC, Eckardt RD, Bender PE, Leonard TB, Straub KM, Newton JF (1987) Biochemical characterization of hepatic microsomal leukotriene B4 hydroxylases. J Biol Chem 262: 1590–1595

    PubMed  CAS  Google Scholar 

  32. Jedlitschky G, Huber M, Volkl A, Muller M, Leier I, Muller J, Lehmann WD, Fahimi HD, Keppler D (1991) Peroxisomal degradation of leukotrienes by beta-oxidation from the omega-end. J Biol Chem 266: 24763–24772

    PubMed  CAS  Google Scholar 

  33. Shirley MA, Murphy RC (1990) Metabolism of leukotriene B4 in isolated rat hepatocytes. Involvement of 2,4-dienoyl-coenzyme A reductase in leukotriene B4 metabolism. J Biol Chem 265: 16288–16295

    PubMed  CAS  Google Scholar 

  34. Powell WS (1986) Novel pathway for the metabolism of 6-trans-leukotriene B4 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 136: 707–712

    Article  PubMed  CAS  Google Scholar 

  35. Powell WS, Gravelle F (1988) Metabolism of 6-trans isomers of leukotriene B4 to dihydro products by human polymorphonuclear leukocytes. J Biol Chem 263: 2170–2177

    PubMed  CAS  Google Scholar 

  36. Wheelan P, Murphy RC (1995) 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 270: 19845–19852

    Article  PubMed  CAS  Google Scholar 

  37. Tokumoto H, Watanabe K, Fukushima D, Shimiza T, Hayaishi O (1982) An NADP-linked 15-hydroxyprostaglandin dehydrogenase specific for prostaglandin D2 from swine brain. J Biol Chem 257: 13576–13580

    PubMed  CAS  Google Scholar 

  38. Wheelan P, Zirrolli JA, Morelli JG, Murphy RC (1993) Metabolism of leukotriene B4 by cultured human keratinocytes. Formation of glutathione conjugates and dihydro metabolites. J Biol Chem 268: 25439–25448

    PubMed  CAS  Google Scholar 

  39. Armstrong RN (1997) Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol 10: 2–18

    Article  PubMed  CAS  Google Scholar 

  40. Guhlmann A, Krauss K, Oberdorfer F, Siegel T, Scheuber PH, Muller J, Csuk-Glanzer B, Ziegler S, Ostertag H, Keppler D (1995) Noninvasive assessment of hepatobiliary and renal elimination of cysteinyl leukotrienes by positron emission tomography. Hepatology 21: 1568–1575

    Article  PubMed  CAS  Google Scholar 

  41. Orning L, Hammarstrom S, Samuelsson B (1980) Leukotriene D: A slow reacting sub-stance from rat basophilic leukemia cells. Proc Natl Acad Sci USA 77: 2014–2017

    Article  PubMed  CAS  Google Scholar 

  42. Bernstrom K, Hammarstrom S (1981) Metabolism of leukotriene D by porcine kidney. J Biol Chem 256: 9579–9582

    PubMed  CAS  Google Scholar 

  43. Keppler D, Guhlmann A, Huber M (1990) Metabolism and actions of leukotrienes in vivo. Prog Appl Microcirc 17: 129–141

    Google Scholar 

  44. Raulf M, Stuning M, Konig W (1985) Metabolism of leukotrienes by L-gamma-glutamyl-transpeptidase and dipeptidase from human polymorphonuclear granulocytes. Immunology 55: 135–147

    PubMed  CAS  Google Scholar 

  45. Yokota K, Shono F, Yamamoto S, Kominami E, Katunuma N (1983) Transformation of leukotriene Dq catalyzed by lysosomal cathepsin H of rat liver. J Biochem 94: 1173–1178

    PubMed  CAS  Google Scholar 

  46. Orning L, Norin E, Gustafsson B, Hammarstrom S (1986) In vivo metabolism of leukotriene Cq in germ-free and conventional rats: Fecal excretion of N-acetyl leukotriene E4. J Biol Chem 261: 766–771

    PubMed  CAS  Google Scholar 

  47. Hagmann W, Denzlinger C, Rapp S, Weckbecker G, Keppler D (1986) Identification of the major endogenous leukotriene metabolite in the bile of rats as N-acetyl leukotriene E4. Prostaglandins 31: 239–251

    Article  PubMed  CAS  Google Scholar 

  48. Sala A, Voelkel N, Maclouf J, Murphy RC (1990) Leukotriene E4 elimination and metabolism in normal human subjects. J Biol Chem 265: 21771–21778

    PubMed  CAS  Google Scholar 

  49. Stene DO, Murphy RC (1988) Metabolism of leukotriene E4 in isolated rat hepatocytes. Identification of beta-oxidation products of sulfidopeptide leukotrienes. J Biol Chem 263: 2773–2778

    PubMed  CAS  Google Scholar 

  50. Orning L (1987) ω-Oxidation of cysteine-containing leukotrienes by rat-liver microsomes: Isolation and characterization of ω-hydroxy and ω-carboxy metabolites of leukotriene E4 and N-acetyl leukotriene E4. Eur J Biochem 170: 77–85

    Article  PubMed  CAS  Google Scholar 

  51. Keppler D, Huber M, Baumert T, Guhlmann A (1989) Metabolic inactivation of leukotrienes. In: G Weber (ed): Advances in enzyme regulation. Pergamon Press, New York, 307–319

    Google Scholar 

  52. Maclouf J, Antoine C, De Caterina R, Sicari R, Murphy RC, Patrignani P, Loizzo S, Patrono C (1992) Entry rate and metabolism of leukotriene C4 into vascular compartment in healthy subjects. Am J Physiol 263: H244–H249

    PubMed  CAS  Google Scholar 

  53. Sala A, Voelkel N, Maclouf J, Murphy RC (1990) Metabolism of radioisotopic variants of LTE4 in human subjects and excretion of urinary metabolites. Adv Prostaglandin Thromboxane Leukot Res 21A: 177–180

    CAS  Google Scholar 

  54. Murphy RC, Sala A, Voelkel N, Maclouf J (1991) Appearance of urinary metabolites of LTE4 in human subjects. Ann NY Acad Sci 629: 105–111

    Article  PubMed  CAS  Google Scholar 

  55. Kumlin M, Sven-Erik D (1990) Characteristics of formation and further metabolism of leukotrienes in the chopped human lung. Biochim Biophys Acta 1044: 201–210

    Article  PubMed  CAS  Google Scholar 

  56. Fauler J, Marx K-H, Kaever V, Frolich JC (1989) Human monocytes convert leukotriene Bq to two dihydro-leukotriene B4-metabolites. Prostaglandins Leukot Essent Fatty Acids 37: 193–196

    Article  PubMed  CAS  Google Scholar 

  57. Serafin WE, Oates JA, Hubbard WC (1983) Metabolism of leukotriene B4 in the monkey. Identification of the principal nonvolatile metabolite in the urine. Prostaglandins 27: 899–911

    Google Scholar 

  58. Mathews WR, Guido DM, Taylor BM, Sun FF (1993) Metabolism of leukotriene B4 by guinea pig eosinophils. Prostaglandins 45: 347–361

    Article  PubMed  CAS  Google Scholar 

  59. Kasimir S, Schonfeld W, Hilger RA, Konig W (1991) Analysis of leukotriene B4 metabolism in human promyelocytic HL-60 cells. Biochem J 279: 283–288

    PubMed  CAS  Google Scholar 

  60. Kaever V, Bruuns J, Wunder J, Damerau B, Zimmer G, Fauler J (1990) Human glomerular mesangial cells inactivate leukotriene B4 by reduction into dihydro-leukotriene B4 metabolites. Life Sci 46: 1465–1470

    Article  PubMed  CAS  Google Scholar 

  61. Kaever V (1987) A novel metabolic pathway for leukotriene B4 in different cell types: primary reduction of double bond. Biochim Biophys Acta 922: 337–344

    Article  PubMed  CAS  Google Scholar 

  62. Wainwright S, Falck JR, Yadagiri P, Powell WS (1990) Stereochemistry of leukotriene B4 metabolites formed by the reductase pathway in porcine polymorphonuclear leukocytes: Inversion of stereochemistry of the 12-hydroxyl group. Biochem 29: 1180–1185

    Article  CAS  Google Scholar 

  63. Wheelan P, Murphy RC (1995) Metabolism of leukotriene B4 in cultured hepatoma cells. Arch Biochem Biophys 321: 381–389

    Article  PubMed  CAS  Google Scholar 

  64. Wheelan P, Simon FR, Murphy RC (1996) GC/MS analysis of oxo and chain-shortened leukotriene B4 metabolites: Leukotriene B4 metabolism in Ito cells. J Mass Spectrom 31: 236–246

    Article  PubMed  CAS  Google Scholar 

  65. Hirata K, Maghni K, Borgeat P, Sirois P (1990) Guinea pig alveolar eosinophils and macrophages produce leukotriene B4 but no peptido-leukotriene. J Immunol 144: 1880–1885

    PubMed  CAS  Google Scholar 

  66. Maas RL, Brash AR, Oates JA (1982) Novel leukotrienes and lipoxygenase products from arachidonic acid. In: B Samuelsson, R Paoletti (eds): Leukotrienes and other lipoxygenase products. Raven Press, New York, 29–44

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO, 80206, USA

    Robert C. Murphy & Joseph A. Hankin

Authors
  1. Robert C. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph A. Hankin
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Cardiopulmonary Pharmacology Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan, 20133, Italy

    Giancarlo Folco

  2. Department of Medical Biochemistry and Biophysics Division of Physiological Chemistry II, Karolinska Institute, Stockholm, 10401, Sweden

    Bengt Samuelsson

  3. National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO, 80206, USA

    Robert C. Murphy

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Basel AG

About this chapter

Cite this chapter

Murphy, R.C., Hankin, J.A. (1999). Metabolism of leukotrienes and formation of new leukotriene structures. In: Folco, G., Samuelsson, B., Murphy, R.C. (eds) Novel Inhibitors of Leukotrienes. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8703-8_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8703-8_4

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9736-5

  • Online ISBN: 978-3-0348-8703-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation