Summary
Leukotrienes are potent mediators of inflammatory and allergic reactions involved, among others, in endotoxin action and shock, tissue trauma, acute liver injury, hepatorenal syndrome, inflammatory bowel disease, acute pancreatitis, and asthma. Studies on metabolism and analysis of these arachidonate metabolites in vivo are a prerequisite for an improved understanding of their role under physiological and pathophysiological conditions and for the development of inhibitors of leukotriene synthesis and of receptor antagonists. Leukotriene C4 and its metabolites, collectively termed the cysteinyl leukotrienes, are predominantly inactivated by the liver. Rapid hepatocellular uptake is followed by partial metabolic inactivation, comprising ω-oxidation and N-acetylation of leukotriene E4, and excretion into bile. A minor portion of the cysteinyl leukotrienes undergoes enterohepatic circulation. In all species investigated so far, hepatobiliary elimination of cysteinyl leukotrienes predominates over renal excretion.
Analysis of the systemic production of cysteinyl leukotrienes in vivo has been accomplished by radioimmunological determination of species-characteristic index metabolites in bile after their separation by high-performance liquid chromatography. The mercapturate N-acetyl-leukotriene E4 is the index metabolite of choice in the rat. In man, leukotriene E4 is the predominant endogenous cysteinyl leukotriene in both bile and urine. The amounts of cysteinyl leukotrienes detected under various pathophysiological conditions may be sufficient to induce known phenomena associated with the respective disease. As shown under experimental conditions, inhibition of leukotriene synthesis or receptor antagonism can serve as therapeutic approaches.
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Abbreviations
- HPLC:
-
High-performance liquid chromatography, Hochleistungsflüssigkeitschromatographie
- LT:
-
Leukotrien
- LTC4 :
-
(S)5-Hydroxy-(R)-6-S-glutathionyl-7,9-trans-11,14-cis-eikosatetraenoat
- LTD4 :
-
(S)5-Hydroxy-(R)-6-S-cysteinylglycyl-7,9-trans-11,14-cis-eikosatetraenoat
- LTE4 :
-
(S)5-Hydroxy-(R)-6-S-cysteinyl-7,9-trans-11,14-cis-eikosatetraenoat
- LTE4NAc:
-
N-Acetyl-LTE4
References
Appelgren LE, Hammarström S (1982) Distribution and metabolism of3H-labeled leukotriene C3 in the mouse. J Biol Chem 257:531–535
Ball HA, Keppler D (1987) ω-Oxidation products of leukotriene E4 in bile and urine of the monkey. Biochem Biophys Res Commun 148:664–670
Baud L, Sraer J, Perez J, Nivez M-P, Ardaillou R (1985) Leukotriene C4 binds to human glomerular epithelial cells and promotes their proliferation in vitro. J Clin Invest 76:374–377
Bernström K, Hammarström S (1986) Metabolism of leukotriene E4 by rat tissues: Formation of N-acetyl-leukotriene E4. Arch Biochem Biophys 244:486–491
Blackwell GJ, Carnuccio R, Di Rosa M, Flower JR, Parente L, Persico P (1980) Macrocortin: A polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature 287:147–149
Brocklehurst WE (1960) The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock. J Physiol 151:416–435
Clancy RM, Dahinden CA, Hugli TE (1984) Oxidation of leukotrienes at the ω-end: Demonstration of a receptor for the 20-hydroxy derivatives of leukotriene B4 on human neutrophils and implications for the analysis of leukotriene receptors. Proc Natl Acad Sci USA 81:5729–5733
Corey EJ, Clark DA, Marfat A (1984) Structure elucidation and total synthesis of the leukotrienes. Chakrin LW, Bailey MD (eds) The leukotrienes, chemistry and biology. Academic Press, Orlando, pp 13–101
Denzlinger C, Rapp S, Hagmann W, Keppler D (1985) Leukotrienes as mediators in tissue trauma. Science 230:330–332
Denzlinger C, Guhlmann A, Hagmann W, Scheuber PH, Scheyerl F, Wilker D, Hammer DK, Keppler D (1986) Cysteinyl leukotrienes undergo enterohepatic circulation. Prostaglandins Leukotrienes Med 21:321–322
Denzlinger C, Guhlmann A, Scheuber PH, Wikler D, Hammer DK, Keppler D (1986) Metabolism and analysis of cysteinyl leukotrienes in the monkey. J Biol Chem 261:15601–15606
Di Rosa M, Flower RJ, Hirata F, Parente L, Russo-Marie F (1984) Antiphospholipase proteins. Prostaglandins 28:441–442
Dixon RAF, Jones RE, Diehl RE, Bennett CD, Kargman S, Rouzer CA (1988) Cloning of the cDNA for human 5-lipoxygenase. Proc Natl Acad Sci USA 85:416–420
Dreyling KW, Hoppe U, Peskar BA, Morgenroth K, Kozuschek W, Peskar BM (1986) Leukotriene synthesis by human gastrointestinal tissues. Biochim Biophys Acta 878:184–193
Ezra D, Foster A, Cirino M, Rokach J, Letts LG (1987) Biliary and urinary excretion of peptide leukotrienes in the domestic pig. Prostaglandins 33:717–725
Feldberg W, Kellaway CH (1938) Liberation of histamine and formation of lysolecithin-like substances by cobra venom. J Physiol 94:187–226
Feuerstein G (1985) Autonomic pharmacology of leukotrienes. J Auton Pharmacol 5:149–168
Fitzsimmons BJ, Rokach J (1988) Lipoxygenase inhibitors and leukotriene receptor antagonists. In: Church M, Robinson C (eds) Advances in eicosanoid reserach — eicosanoids in inflammatory conditions of the lung, skin and joints. MTP Press, Lancaster, pp 147–190
Flower RJ, Blackwell GJ (1979) Antiinflammatory steroids induce biosynthesis of a pospholipase A2 inhibitor which prevents prostaglandin generation. Nature 278:456–459
Ford-Hutchinson AW (1985) Leukotrienes: Their formation and role as inflammatory mediators. Fed Proc 44:25–29
Guhlmann A, Hagmann W, Keppler D (1987) Enterohepatic circulation of N-acetyl-leukotriene E4. Prostaglandins 34:63–70
Hagmann W, Denzlinger C, Keppler D (1984) Role of peptide leukotrienes and their hepatobiliary elimination in endotoxin action. Circ Shock 14:223–235
Hagmann W, Denzlinger C, Keppler D (1985) Production of peptide leukotrienes in endotoxin shock. FEBS Lett 180:309–313
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
Hagmann W, Steffan A-M, Kirn A, Keppler D (1987) Leukotrienes as mediators in frog virus 3-induced hepatitis in rats. Hepatology 7:732–736
Hagmann W, Keppler D (1988) Leukotrienes and other eicosanoids in liver pathophysiology. In: Arias IM, Jakoby WB, Popper H, Schachter D, and Shafritz DA (eds) The liver: biology and pathobiology. Raven Press, New York, pp 793–806
Hammarström S (1983) Leukotrienes. Annu Rev Biochem 52:355–377
Hammarström S, Örning L, Bernström K (1985) Metabolism of leukotrienes. Mol Cell Biochem 69:7–16
Harper TW, Garrity MJ, Murphy RC (1986) Metabolism of leukotriene B4 in isolated rat hepatocytes. J Biol Chem 261:5414–5418
Hirata F, Schiffmann E, Venkatasubramanian K, Salomon D, Axelrod J (1980) A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci USA 77:2533–2536
Huber M, Guhlmann A, Jansen PLM, Keppler D (1987a) Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion. Hepatology 7:224–228
Huber M, Kästner S, Schölmerich J, Keppler D (1987b) Enhanced urinary excretion of cysteinyl leukotrienes in patients with hepatorenal syndrome. J Hepatol 5:S34
Huber M, Keppler D (1987) Inhibition of leukotriene D4 catabolism by D-penicillamine. Eur J Biochem 167:73–79
Huber M, Keppler D (1988) Leukotrienes and the mercapturate pathway. In: Sies H, Ketterer B (eds) Glutathione conjugation: its mechanism and biological significance. Academic Press, London, pp 449–470
Jakschik BA, Harper T, Murphy RC (1982) Leukotriene C4 and D4 formation by particulate enzymes. J Biol Chem 257:5346–5349
Keppler A, Örning L, Bernstörm K, Hammarström S (1987) Endogenous leukotriene D4 formation during anaphylactic shock in the guinea pig. Proc Natl Acad Sci USA 84:5903–5907
Keppler D, Hagmann W, Rapp S, Denzlinger C, Koch HK (1985) The relation of leukotrienes to liver injury. Hepatology 5:883–891
Keppler D, Hagmann W, Rapp S (1987) Role of Leukotrienes in endotoxin action in vivo. Rev Inf Diseases 9:S580-S584
Keppler D, Huber M, Weckbecker G, Hagmann W, Denzlinger C, Guhlmann A (1987) Leukotriene C4 metabolism by hepatoma cells and liver. Adv Enzyme Regul 26:211–224
Keppler D, Huber M, Hagmann W, Ball HA, Guhlmann A, Kästner S (1988) Metabolism and analysis of endogenous cysteinyl leukotrienes. Ann NY Acad Sci 524:68–74
Kozak EM, Tate SS (1982) Glutathione-degrading enzymes of microvillus membranes. J Biol Chem 257:6322–6327
Kragballe K, Desjarlais L, Voorhees JJ (1985) Leukotrienes B4, C4 and D4 stimulate DNA synthesis in cultured human epidermal keratinocytes. Br J Derm 113:43–52
Lewis RA, Drazen JM, Austen FK, Toda M, Brion F, Marfat A, Corey JE (1981) Contractile activities of structural analogs of leukotrienes C and D: role of the polar substituents. Proc Natl Acad Sci USA 78:4579–4583
Lewis RA, Austen KF (1984) The biologically active leukotrienes. Biosynthesis, metabolism, receptors, functions, and pharmacology. J Clin Invest 73:889–897
Matsumoto T, Funk CD, Rådmark O, Höög J-O, Jörnvall H, Samuelsson B (1988) Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci USA 85:26–30
Murphy RC, Hammarström S, Samuelsson B (1979) Leukotriene C: A slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 76:4275–4279
Örning L, Kaijser L, Hammarström S (1985) In vivo metabolism of leukotriene C4 in man: Urinary excretion of leukotriene E4. Biochem Biophys Res Commun 130:214–220
Örning L, Norin E, Gustafsson B, Hammarström S (1986) In vivo metabolism of leukotrine C4 in germ-free and conventional rats. Fecal excretion of N-acetylleukotriene E4. J Biol Chem 261:766–771
Örning L (1987b) 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-acetylleukotriene E4. Eur J Biochem 170:77–85
Ormstad K, Uehara N, Orrenius S, Örning L, Hammarström S (1982) Uptake and metabolism of leukotriene C3 by isolated rat organs and cells. Biochem Biophys Res Commun 104:1434–1440
Peskar BM, Dreyling KW, Peskar BA, May B, Goebell H (1986) Enhanced formation of sulfidopeptide-leukotrienes in ulcerative colitis and Crohn's disease: Inhibition by sulfasalazine and 5-aminosalicylic acid. Agent Actions 18:381–383
Rådmark O, Malmsten C, Samuelsson B (1980) Leukotriene A4: Enzymatic conversion to leukotriene C4. Biochem Biophys Res Commun 96:1679–1687
Rouzer CA, Matsumoto T, Samuelsson B (1986) Single protein from human leukocytes posseses 5-lipoxygenase and leukotriene A4 synthase activities. Proc Natl Acad Sci USA 83:857–861
Samuelsson B (1983) Leukotrienes: Mediators of immediate hypersensitivity reactions and inflammation. Science 220:568–575
Samuelsson B, Dahlén S-E, Lindgren J-Å, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237:1171–1176
Scheuber PH, Denzlinger C, Wilker D, Beck G, Keppler D, Hammer DK (1987) Cysteinyl leukotrienes as mediators of staphylococcal enterotoxin B in the monkey. Eur J Clin Invest 17:455–459
Söderström M, Hammarström S, Mannervik B (1988) Leukotriene C synthase in murine mastocytoma cells: a novel enzyme distinct from cytosolic and microsomal glutathione transferases. Biochem J 250:713–718
Stene DO, Murphy RC (1988) Metabolism of leukotriene E4 in isolated rat hepatocytes. Identification of β-oxidation products of sulfidopeptide leukotrienes. J Biol Chem 263:2773–2778
Uehara N, Ormstad K, Örning L, Hammarström S (1983) Characteristics of the uptake of cysteine-containing leukotrienes by isolated hepatocytes. Biochim Biophys Acta 732:69–74
Weckbecker G, Keppler D (1986) Leukotriene C4 metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes. Eur J Biochem 154:559–562
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Vortrag anläßlich der Preis-Verleihung am 30. Oktober 1987
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Keppler, D. Stoffwechsel und Analyse von Leukotrienen in vivo. Klin Wochenschr 66, 997–1004 (1988). https://doi.org/10.1007/BF01733441
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DOI: https://doi.org/10.1007/BF01733441