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Digestive Diseases and Sciences

, Volume 41, Issue 2, pp 250–255 | Cite as

Different protective effects of tauroursodeoxycholate, ursodeoxycholate, and 23-methyl-ursodeoxycholate against taurolithocholate-induced cholestasis

  • Ulrich Baumgartner
  • Jurgen Schölmerich
  • Markus Sellinger
  • Martina Reinhardt
  • Günter Ruf
  • Eduard-Heinrich Farthmann
Pancreatic And Biliary Disorders

Abstract

The coinfusion of tauroursodeoxycholate (TUDC) prevents taurolithocholate (TLC) -induced cholestasis. 23-Methyl-ursodeoxycholate (MUDC) is a side-chain derivative of ursodeoxycholate (UDC). If conjugation with taurine is important for the protective effect of UDC, then MUDC may not be as able as TUDC to prevent TLC-induced cholestasis since it is poorly amidated by the liver. To answer this question, isolated livers of adult Sprague-Dawley rats were coinfused with MUDC (UDC, TUDC) and TLC. After 15 min, inflow rates of the bile acids were doubled. In further experiments taurine in excess was added to the coinfused bile acids. The uptake of bile acids was >90% in all groups, irrespective of whether they were perfused alone or in combination. Single perfusion of TLC caused a rapid decrease in bile flow. UDC and MUDC were hypercholeretic; TUDC moderately choleretic. During coinfusion experiments, TUDC not only completely abolished cholestasis but in addition increased bile flow and biliary bile acid secretion. UDC did prevent TLC cholestasis at the lower inflow rates. At high inflow rates, bile flow decreased significantly. Addition of taurine to this bile acid combination did not significantly improve the anticholestatic effect of UDC. At low and high infusion rates of MUDC, cholestasis induced by TLC was reduced very little. Cumulative bile flow over 30 min fell by ≈70% as compared to that of singly perfused MUDC. Addition of taurine to the coinfused MUDC/TLC slightly, but significantly, improved the anticholestatic effect of MUDC. Since MUDC is by far less protective than UDC (and TUDC) despite similar physicochemical properties, it is concluded that taurine conjugation of UDC seems to be a prerequisite to prevent TLC-induced cholestasis. The results imply that treatment of cholestatic liver diseases with taurine-conjugated UDC might be more appropriate than with unconjugated UDC in cases where taurine conjugation is defective or where taurine depletion has occurred.

Key words

ursodeoxycholate bile acid coinfusion bile acid metabolism isolated liver perfusion cholestasis 

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References

  1. 1.
    Leuschner U, Fischer H, Kurtz W, Güldütuna S, Hübner K, Hellstern A, Gatzen M, Leuschner M: Ursodeoxycholic acid in primary biliary cirrhosis: Results of a controlled double-blind trial. Gastroenterology 97:1268–1274, 1989PubMedGoogle Scholar
  2. 2.
    Bellentani S, Tabarroni G, Barchi T, Ferretti I, Fratti N, Villa E, Manenti F: Effect of ursodeoxycholic acid treatment on alanine aminotransferase and gammaglutamyltranspeptidase serum levels in patients with hyerptransaminaseemia—results from a double-blind controlled trial. J Hepatol 8:7–12, 1989PubMedGoogle Scholar
  3. 3.
    Bateson MC, Ross PE, Diffey BL: Ursodeoxycholic acid in primary biliary cirrhosis. Lancet 1:898–899, 1989Google Scholar
  4. 4.
    Yoon YB, Hagey LR, Hofmann AF, Gurantz D, Michelotti EL, Steinbach JH: Effect of side-chain shortening on the physiologic properties of bile acids: Hepatic transport and effect on biliary secretion of 23-norursodeoxycholate in rodents. Gastroenterology 90:837–852, 1986PubMedGoogle Scholar
  5. 5.
    Roda A, Grigolo B, Aldinin R, Simoni P, Pellicciari R, Natalini B, Balducci R: Bile acids with a cyclopropyl-containing side chain. 4. Physicochemical and biological properties of the four diastereoisomers of 3α,7β-dihydroxyd-22,23-methylene-5β-cholan-24-oic acid. J Lipid Res 28:1384–1397, 1987PubMedGoogle Scholar
  6. 6.
    Roda A, Aldini R, Grigolo B, Simoni P, Roda E, Pellicciari R, Lenzi PL, Natalini B: 23-Methyl-3α,7β-dihydroxy-5β-cholan-24-oic acid: Dose-response study of biliary secretion in rat. Hepatology 8:1571–1576, 1988PubMedGoogle Scholar
  7. 7.
    Castagnola V, Frigerio G, Pelicciari R, Roda A: New derivatives of bile acids, process for the production thereof corresponding pharmaceutical compositions. European Patent 135:782 A2, 1984Google Scholar
  8. 8.
    Clerici C, Dozzini G, Distrutti E, Gentili G, Sadeghpour BM, Natalini B, Pellicciari R, Rizzoli R, Roda A, Pelli MA, Morelli A: Effect of intraduodenal administration of 23-methyl-UDCA diastereoisomers on bile flow in hamsters. Dig Dis Sci 37:791–798, 1992PubMedGoogle Scholar
  9. 9.
    Schölmerich J, Kitamura S, Baumgartner U, Miyai K, Gerok W: Taurohyocholate, taurocholate and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver. Res Exp Med 190:121–129, 1990Google Scholar
  10. 10.
    Schölmerich J, Baumgartner U, Miyai, Gerok W: Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver. J Hepatol 10:280–283, 1990PubMedGoogle Scholar
  11. 11.
    Schmucker DL, Ohta M, Kanai S, Sato Y, Kitani K: Hepatic injury induced by bile salts: correlations between biochemical and morphological events. Hepatology 12:1216–1221, 1990PubMedGoogle Scholar
  12. 12.
    Heuman DM, Mills S, McCall J, Hylemon PB, Pandak WM, Vlahcevic ZR: Conjugates of urosdeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts.In vivo studies in the rat. Gastroenterology 100:203–211, 1991PubMedGoogle Scholar
  13. 13.
    Thibault N, Maurice M, Maratrat M, Cordier A, Feldmann G, Ballet F: Effect of tauroursodeoxycholate on actin filament alteration induced by cholestatic agents. A study in isolated rat hepatocyte couplets. J Hepatol 19:367–376, 1993PubMedGoogle Scholar
  14. 14.
    Beuers U, Nathanson MH, Isales CM, Boyer JL: Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest 92:2984–2993, 1993PubMedGoogle Scholar
  15. 15.
    Güldütuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U: Molecular aspects of membrane stabilization by urosdeoxycholate. Gastroenterology 104:1736–1744, 1993Google Scholar
  16. 16.
    Tserng KY, Hachey DL, Klein PD: An improved procedure for the synthesis of glycine and taurine conjugates of bile acids. J Lipid Res 18:404–407, 1977PubMedGoogle Scholar
  17. 17.
    Baumgartner U, Miyai K, Hardison WGM: Greater taurodeoxycholate biotransformation during backward perfusion of rat liver. Am J Physiol 251:G431-G435, 1986PubMedGoogle Scholar
  18. 18.
    Schölmerich J, Roda A, DeLuca M: Immobilized enzymes for assaying bile acids. Methods Enzymol 133:215–229, 1986PubMedGoogle Scholar
  19. 19.
    Baumgarnter U, Schölmerich J, Leible P, Farthmann EH: Cholestasis, metabolism and biliary lipid secretion during perfusion of rat liver with different bile salts. Biochim Biophys Acta 1125:142–149, 1992PubMedGoogle Scholar
  20. 20.
    Baumgartner U, Hardison WGM, Miyai K: Reduced cholestatic potency of taurolithocholate during backward perfusion of the rat liver. Lab Invest 56:576–582, 1987PubMedGoogle Scholar
  21. 21.
    Kitani K, Kanai S: Biliary transport maximum of tauroursodeoxycholate is twice as high as that of taurocholate in the rat. Life Sci 29:269–275, 1981PubMedGoogle Scholar
  22. 22.
    Barnwell SG, Lowe PJ, Coleman R: Effect of taurochenodeoxycholate or tauroursodeoxycholate upon biliary outputs of phospholipids and plasma membrane enzymes, and the extent of cell damage, in isolated perfused rat livers. Biochem J 216:107–111, 1983PubMedGoogle Scholar
  23. 23.
    Kitani K, Kanai S, Ohta M, Sato Y: Differing transport maxima values for taurine-conjugated bile salts in rats and hamsters. Am J Physiol 251:G852-G858, 1986PubMedGoogle Scholar
  24. 24.
    Hofmann AF, Roda A: Physicochemical properties of bile acids and their relationship to biological properties: An overview of the problem. J Lipid Res 25:1477–1489, 1984PubMedGoogle Scholar
  25. 25.
    Tavaloni N, Sarkozi L, Jones MJT: Choleretic effects of differently structured bile acids in the guinea pig. Proc Soc Exp Biol Med 178:60–65, 1985PubMedGoogle Scholar
  26. 26.
    O'Maille ERL, Kozmary SV, Hofmann AF, Gurantz D. Differing effects of norcholate and cholate on bile flow and biliary lipid secretion in the rat. Am J Physiol 246:G67-G71, 1984PubMedGoogle Scholar
  27. 27.
    Dumont M, Erlinger S, Uchman S: Hypercholeresis induced by ursodeoxycholic acid and 7-ketolithocholic acid in the rat: Possible role of bicarbonate transport. Gastroenterology 79:82–89, 1980PubMedGoogle Scholar
  28. 28.
    Danzinger RG, Nakagaki M, Hofmann AF, Ljungwe EB: Differing effects of hydroxy-7-oxotaurine-conjugated bile acids on bile flow and biliary lipid secretion in dogs. Am J Physiol 246:G166-G172, 1984PubMedGoogle Scholar
  29. 29.
    Gurantz D, Hofmann AF: Influence of bile acid structure on bile flow and biliary lipid secretion in the hamster. Am J Physiol 247:G736-G748, 1984PubMedGoogle Scholar
  30. 30.
    Zouboulis-Vafiadis I, Dumont M, Erlinger S: Hypercholeretic bile acids. Hepatic metabolism and effect on bile secretion of 23-methyl-ursodeoxycholic acid.In Bile Acids and the Liver. Paumgartner G, A Stiehl, W Gerok (eds). Lancaster, MTP Press Limited, pp 195–197, 1986Google Scholar
  31. 31.
    Tsukahara K, Kanai S, Ohta M, Kitani K: Taurine conjugate of urosdeoxycholate plays a major role in the hepatoprotective effect against cholestasis induced by taurochenodeoxycholate in rats. Liver 13:262–269, 1993PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Ulrich Baumgartner
    • 1
    • 2
  • Jurgen Schölmerich
    • 1
    • 2
  • Markus Sellinger
    • 1
    • 2
  • Martina Reinhardt
    • 1
    • 2
  • Günter Ruf
    • 1
    • 2
  • Eduard-Heinrich Farthmann
    • 1
    • 2
  1. 1.Department of SurgeryUniversity of FreiburgFreiburgGermany
  2. 2.Department of Internal MedicineUniversity of RegensburgGermany

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