Mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases

Alimentary Pharmacology and Therapeutics

Volumn 13, Issue 8, 1999, Pages 979-995

  Trauner, M ^a   Graziadei, I W ^b  

^a MEDICAL UNIVERSITY OF GRAZ   (Austria)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOL; BILE ACID; CYCLOSPORIN; URSODEOXYCHOLIC ACID; CHOLAGOGUE;

ALCOHOL LIVER DISEASE; APOPTOSIS; BILE SECRETION; CELL PROTECTION; CHRONIC LIVER DISEASE; CLINICAL TRIAL; CYSTIC FIBROSIS; DRUG ABSORPTION; DRUG EFFICACY; DRUG MECHANISM; EXOCYTOSIS; GRAFT REJECTION; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNOMODULATION; INTRAHEPATIC CHOLESTASIS; LIVER TRANSPLANTATION; ORAL DRUG ADMINISTRATION; PREGNANCY; PRIMARY BILIARY CIRRHOSIS; PRIMARY SCLEROSING CHOLANGITIS; PRIORITY JOURNAL; REVIEW; SURVIVAL; TOTAL PARENTERAL NUTRITION; VIRUS HEPATITIS; ANIMAL; CHRONIC DISEASE; FEMALE; LIVER DISEASE;

ANIMALS; CHOLAGOGUES AND CHOLERETICS; CHOLESTASIS, INTRAHEPATIC; CHRONIC DISEASE; FEMALE; HUMANS; LIVER DISEASES; PREGNANCY; URSODEOXYCHOLIC ACID;

EID: 0033172845     PISSN: 02692813     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2036.1999.00596.x     Document Type: Review

References (188)

1. 1 Shoda M. Über die Ursodesoxycholsäure aus Bärengallen und ihre physiologische Wirkung. J Biochem 1927; 7: 505-10.
2. 2 Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol 1994; 29(Suppl. 204): 1-15.
3. 3 Poupon R, Poupon RE. Ursodeoxycholic acid therapy of chronic cholestatic conditions in adults and children. Pharmacol Ther 1995; 66: 1-15.
4. 4 Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: Potential mechanisms of action and therapeutic applications. Hepatology 1998; 28: 1449-53.
5. 5 Iwasaki T. Über die Konstitution der Ursodesoxycholsäure. Z Physiol Chem 1936; 244: 181-91.
6. 6 Sugata F, Shimugu M. Retrospective studies on gallstones disappearance. Jpn J Gastroenterol 1974; 71: 75-80.
7. 7 Bachrach WH, Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Dig Dis Sci 1982; 24: 737-61.
8. 8 Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hubner K. Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 1985; 30: 642-9.
9. 9 Mijayi K, Akiyama T, Ito M, Urakawa T, Shimaji Y. The effect of ursodeoxycholic acid on liver functions in patients with chronic liver disease. A double-blind study in one institution and the study on the effect on hepatic blood flow. Rinsho Kenkyu 1976; 53: 1395-403.
10. 10 Yamanaka M, Oto M, Obata H, et al. The examination of the therapeutic efficacy of ursodeoxycholic acid on chronic hepatitis. A double-blind study. Shindan Chiryo 1976; 64: 2150-7.
11. 11 Fisher MM, Paradine ME, Influence of ursodeoxycholic acid on biochemical parameters in cholestatic disease, Gastroenterology 1986; 90: 1725.
12. 12 Poupon R, Poupon RE, Calmus Y, Chretien Y, Ballet F, Darnis F. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1987; 1: 834-6.
13. 13 Leuschner U, Fischer H, Kurtz W, et al. Ursodeoxycholic acid in primary biliary cirrhosis: Results of a controlled double-blind trial. Gastroentrology 1989; 97: 1268-74.
14. 14 Radominska A, Treat S, Little J. Bile acid metabolism and the pathophysiology of cholestasis. Semin Liver Dis 1993; 13: 219-34.
15. 15 Reichen J, Krähenbühl S, Zimmermann H. Impact of cholestasis on hepatic function; retention of cholephiles and their potential targets. In: Gentilini P et al., eds. Cholestasis. Amsterdam: Elsevier Science, 1994: 167-75.
16. 16 Hay DW, Carey M. Chemical species of lipids in bile. Hepatology 1990; 12: S6-16.
17. 17 Queneau PE, Montet JC. Hepatoprotection by hydrophilic bile salts. J Hepatol 1994; 21: 260-8.
18. 18 Beuers U, Kullak-Ublick GA, Paumgartner G. Mechanism of action of ursodeoxycholic acid in cholestatic syndromes. In: Alvaro D, Benedetti A, Strazzabosco M, eds. Vanishing Bile Duct Syndrome. Pathophysiology and Treatment. Dordrecht: Kluwer Academic Publishers, 1997: 230-9.
19. 19 Greim H, Czygan P, Schaffner F, Popper H. Determination of bile acids in needle biopsies of human liver. Biochem Med 1973; 8: 280-6.
20. 20 Setchell KDR, Rodrigues CMP, Clerici C, et al. Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei, Gastroenterology 1997; 112: 226-35.
21. 21 Fromm H. Cholestasis: Pathogenic role and therapeutic action of bile acids. In: Gentilini P, et al., eds. Cholestasis. Amsterdam: Elsevier Science. 1994: 239-43.
22. 22 Rubin RA, Kowalski TE, Khandelwal M, Malet PF. Ursodiol for hepatobiliary disorders. Ann Intern Med 1994; 121: 207-18.
23. 23 Rodrigues CMP, Kren BT, Steer CJ, Setchell KDR. Tauroursodeoxycholate increases rat liver ursodeoxycholate levels and limits lithocholate formation better than ursodeoxycholate. Gastroenterology 1995; 109: 564-72.
24. 24 Cirillo NW, Zwas FR. Ursodeoxycholic acid in the treatment of chronic liver disease. Am J Gastroenterol 1994; 89: 1447-52.
25. 25 Leuschner U, Ursodeoxycholic acid therapy in primary biliary cirrhosis. Scand J Gastroenterol 1994; 29(Suppl. 204): 40-6.
26. 26 Batta AK, Salen G, Arora R, et al. Effect of ursodeoxycholic acid on bile acid metabolism in primary biliary cirrhosis. Hepatology 1989; 10: 414-19.
27. 27 Batta AK, Arora R, Salen G, Tint GS, Eskreis D, Katz S. Characterization of serum and urinary bile acids in patients with primary biliary cirrhosis by gas-liquid chromatography-mass spectrometry: Effect of ursodeoxycholic acid treatment, J Lipid Res 1989; 30: 1553-62.
28. 28 Stiehl A, Rudolph G, Raedsch R, et al. Ursodeoxycholic acid-induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis. Hepatology 1990; 12: 492-7.
29. 29 Stiehl A, Raedsch R, Rudolph G. Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids. Gastroenterology 1990; 98: 424-8.
30. 30 Crosignani A, Podda M, Battezzati PM, et al. Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acid administration. Hepatology 1991; 14: 1000-7.
31. 31 Poupon RE, Chretien Y, Poupon R, Paumgartner G. Serum bile acids in primary biliary cirrhosis: Effect of ursodeoxycholic acid therapy. Hepatology 1993; 17: 599-604.
32. 32 Combes B, Carithers RL, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995; 22: 759-66.
33. 33 Beuers U, Spengler U, Zwiebel FM, Pauletzki J, Fischer S, Paumgartner G. Effect of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease. Hepatology 1992; 15: 603-8.
34. 34 Marteau P, Chazouilleres O, Myara A, Jian R, Rambaud JC, Poupon R. Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man. Hepatology 1990; 12: 1206-8.
35. 35 Eusufzai S, Ericsson S, Crederlund T, Einarsson K, Angelin B. Effect of ursodeoxycholic acid treatment on ileal absorption of bile acids in man as determined by SeHCAT test. Gut 1991; 32: 1044-8.
36. 36 Rudolph G, Endele R, Senn M, Stiehl A. Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis, Hepatology 1993; 17: 1028-32.
37. 37 Mazzella G, Parini P, Bazzoli F, et al. Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis. Dig Dis Sci 1993; 38: 896-902.
38. 38 Holsti P. Cirrhosis of the liver induced in rabbits by gastric instillation of 3-monohydroxycholynic acid. Nature 1960; 186: 250.
39. 39 Javitt JB. Cholestasis in rats induced by taurolithocholale. Nature 1966; 210: 1262-3.
40. 40 Patel T, Roberts LR, Jones BA, Gores GJ. Dysregulation of apoptosis as a mechanism of liver disease: an overview, Semin Liver Dis 1998; 18: 105-14.
41. 41 Heuman DM, Milk AS, McCall J, Hylemon PB, Pandak WM, Vlahevic ZR. Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat. Gastroenterology 1991; 100: 203-11.
42. 42 Heuman DM, Pandak WM, Hylemon PB, Vlahevic ZR. Conjugates of ursodeoxycholate protect against cytotoxicity of more Hydrophobic bile salts: In vitro studies in rat hepatocytes and human erythrocytes. Hepatology 1991; 14: 920-6.
43. 43 Heuman DM, Bajaj R. Ursodeoxycholate conjugates protect against disruption of cholesterol-rich membranes by bile salts. Gastroenterology 1994; 106: 1533-41.
44. 44 Galle PR, Theilmann L, Raedsch R, Otto G, Stiehl A. Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology 1990; 12: 486-91.
45. 45 Güldütuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U. Molecular aspects of membrane stabilization by ursodeoxycholate. Gastroenterology 1993; 104: 1736-44.
46. 46 Kitani K, Kanai S. Tauroursodeoxycholate prevents taurocholate-induced cholestasis. Life Sci 1982; 30: 515-23.
47. 47 Schoelmerich J, Baumgartner U, Miyai K, Gerok W. Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver. J Hepatol 1990; 10: 280-3.
48. 48 Poo JL, Feldmann G, Erlinger S, et al. Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat. Gastroenterology 1992; 102: 1752-9.
49. 49 Neuman MG, Cameron RG, Shear NH, Bellentani S, Tiribelli C. Effect of tauroursodeoxycholic and ursodeoxyeholic acid on ethanol-induced cell injuries in the human Hep G2 cell line. Gastroenterology 1995; 109: 555-63.
50. 50 Vendemiale G, Grattagliano I, Signorile A, Altomare E. Ethanol-induced changes of intracellular thiol compartmentation and protein redox status in the rat liver: Effect of tauroursodeoxycholate. J Hepatol 1998; 28: 46-53.
51. 51 Peterson TC, Slysz G, Isbrucker R, The inhibitory effect of ursodeoxyeholic acid and pentoxifylline on platelet derived growth factor-stimulated proliferation is distinct from an effect by cyclic AMP. Immunopharmacology 1998; 39: 181-91.
52. 52 Hillaire S, Boucher E, Calmus Y, et al. Effects of bile acids and cholestasis on major histocompatibility complex class I in human and rat hepatocytes. Gastroenterology 1994; 107: 781-8.
53. 53 Heuman DM, Bajaj R, Lin Q, Adsorption of mixtures of bile salt taurine conjugates to lecithin-cholesterol membranes: Implications for bile salt toxicity and cytoprotection. J Lipid Res 1996; 37: 562-73.
54. 54 Oude Elferink RPJ, Groen AK. The role of mdr2 P-glycoprotein in biliary lipid secretion. Cross-talk between cancer research and biliary physiology. J Hepatol 1995; 23: 617-25.
55. 55 Oude Elferink RPJ. Tytgat GNJ. Groen AK. The role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB J 1997; 11: 19-28.
56. 56 Puglielli L, Amigo L, Arrese M, et al. Protective role of biliary cholesterol and phospolipid lamellae against bile acid-induced cell damage. Gastroenterology 1994; 107: 244-54.
57. 57 Benedetti A, Alvaro D, Bassotti C, et al. Cytotoxicity of bile salts against biliary epithelium: a study in isolated bile ductule fragments and isolated perfused rat liver. Hepatology 1997; 26: 9-21.
58. 58 van Nieuwkerk CMJ, Oude Elferink RPJ. Groen AK, et al. Effects of ursodeoxycholate and cholate feeding on liver diseases in FVB mice with disrupted mdr2 P-glycoprotein gene. Gastroenterology 1996; 111: 165-71.
59. 59 de Vree JML, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 1998; 95: 282-7.
60. 60 Jacquemin E, Hermans D, Myara A, et al. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology 1997; 25: 519-23.
61. 61 Que FG, Gores GJ. Cell death by apoptosis: Basic concepts and disease relevance for the gastroenterologist. Gastroenterology 1996; 110: 1238-43.
62. 62 Celli A, Que FG. Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma. Semin Liver Dis 1998; 18: 177-85.
63. 63 Faubion WA, Gores GJ. Death receptors in liver biology and pathobiology. Hepatology 1999; 29: 1-4.
64. 64 Faubion WA, Guicciardi ME, Miyoshi H, et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 1999; 103: 137-45.
65. 65 Harada K, Ozaki S, Gershwin ME, Nakanuma Y. Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis. Hepatology 1997; 26: 1399-405.
66. 66 Graham AM, Dollinger MM, Howie SE, Harrison DJ. Bile duct cells in primary biliary cirrhosis are 'primed' for apoptosis. Eur J Gastroenterol Hepatol 1998; 10: 553-7.
67. 67 Benz C, Angermueller S, Toex U, et al. Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis and cytolysis in rat hepatocytes. J Hepatol 1998; 28: 99-106.
68. 68 Rodrigues CMP, Fan G, Ma X, Kren BT, Steer CJ. A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest 1998; 101: 2790-9.
69. 69 Lemasters JJ. The mitochondrial permeability transition: From biochemical curiosity to pathophysiological mechanism. Gastroenterology 1998; 115: 783-6.
70. 70 Lieser MJ, Park J, Natori S, Jones BA, Bronk SF, Gores GJ. Cholestasis confers resistance to the rat liver mitochondrial permeability transition. Gastroenterology 1998; 115: 693-701.
71. 71 Koga H, Sakisaka S, Ohishi M, Sata M, Tanikawa K. Nuclear DNA fragmentation and expression of Bcl-2 in primary biliary cirrhosis. Hepatology 1997; 25: 1077-84.
72. 72 Guicciardi ME, Gores GJ. Is ursodeoxycholic acid an anti-apoptotic drug? Hepatology 1998; 28: 1721-3.
73. 73 Calmus Y, Arvieux C, Gane P, et al. Cholestasis induces major histocompatibility complex class I expression in hepatocytes. Gastroenterology 1992; 102: 1371-7.
74. 74 Calmus Y, Weill B, Ozier Y, Chereau C, Houssin D, Poupon R. Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic adds in the mouse. Gastroenterology 1992; 103: 617-21.
75. 75 Calmus Y, Guechot J, Podevin P, Bonnefis MT, Giboudeau J, Poupon R. Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6, and tumor necrosis factor-α production by monocytes. Hepatology 1992; 16: 719-23.
76. 76 Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: Effect of ursodeoxycholic acid. Hepatology 1990; 11: 12-15.
77. 77 Terasaki S, Nakanuma Y, Ogino H, Unoura M, Kobayashi K. Hepatocellular and biliary expression of HLA antigens in primary biliary cirrhosis before and after ursodeoxycholic acid therapy. Am J Gastroenterol 1991; 86: 1194-9.
78. 78 Yoshikawa M, Tsujii T, Matsumura K, et al. Immunomodulatory effects of ursodeoxycholic acid on immune response. Hepatology 1992; 16: 358-64.
79. 79 Bergamini A, Dini L, Baiocchi L, et al. Bile acids with differing hydrophilic-hydrophobic properties do not influence cytokine production by human monocytes and murine Kupffer cells. Hepatology 1997; 25: 927-33.
80. 80 Tanaka H, Makino I. Ursodeoxycholic acid-dependent activation of the glucocorticoid receptor, Biochem Biophys Res Commun 1992; 188: 942-8.
81. 81 Mitsuyoshi H, Nakashima T, Inaba K, et al. Ursodeoxycholic acid enhances glucocorticoid-induced tyrosinc aminotransferase-gene expression in cultured rat hepatocytes. Biochem Biophys Res Commun 1997; 240: 732-6.
82. 82 Invernizzi P, Salzman AL, Szabo V, Ueta I, O'Connor M, Setchell KD. Ursodeoxycholate inhibits induction of NOS in human intestinal epithelial cells and in vivo. Am J Physiol 1997; 273: G131-8.
83. 83 Poupon RE, Balkan B, Eschwege E, Poupon R and the UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991; 324: 1548-54.
84. 84 Kisand KE, Karvonen AL, Vuoristo M, et al. Ursodeoxycholic acid treatment lowers the serum level of antibodies against pyruvate dehydrogenase and influences their inhibitory capacity for the enzyme complex in patients with primary biliary cirrhosis. J Mol Med 1996; 74: 269-74.
85. 85 Kim WR, Poterucha JJ, Jorgensen RA, et al. Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation. Hepatology 1997; 26: 22-6.
86. 86 Invernizzi P, Crosignani A, Battezzati PM, et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and negative primary biliary cirrhosis. Hepatology 1997; 25: 1090-5.
87. 87 Kuerktschiev D, Subat S, Adler D, Schentke KU. Immunomodulating effect of ursodeoxycholic acid therapy in patients with primary biliary cirrhosis. J Hepatol 1993; 18: 373-7.
88. 88 Nishigaki Y, Ohnishi H, Moriwaki H, Muto Y. Ursodeoxycholic acid corrects defective natural killer activity by inhibiting prostaglandin E2 production in primary biliary cirrhosis. Dig Dis Sci 1996; 41: 1487-93.
89. 89 Ohiwa T, Katagiri K, Hoshino M, Hayakawa T, Nakai T. Tauroursodeoxycholate and tauro-beta-muricholate exert cytoprotection by reducing intrahepatocyte taurochenodeoxycholate content. Hepatology 1993; 17: 470-6.
90. 90 Deroubaix X, Coche T, Depiereux E, Feytmans E. Saturation of hepatic transport of taurocholate in rats in vivo. Am J Physiol 1991; 260: G189-96.
91. 91 Häussinger D, Hallbrucker C, Saha N, Lang F, Gerok W. Cell volume and bile acid excretion. Biochem J 1992; 288: 681-9.
92. 92 Kitani K, Ohta M, Kanai S. Tauroursodeoxycholate prevents biliary protein excretion induced by other bile salts in the rat. Am J Physiol 1985; 248: G407-17.
93. 93 Galan AI, Jimenez R, Munoz ME, Gonzales J. Effect of ursodeoxycholate on maximal biliary secretion of bilirubin in the rat. Biochem Pharmacol 1990; 39: 1175-80.
94. 94 Colombo C, Castellani MR, Balistreri WF, Seregni E, Assaisso ML, Giunta A. Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease. Hepatology 1992; 15: 677-84.
95. 95 Jazrawi RP, de Caestecker JS, Goggin PM, et al. Kinetics of hepatic bile acid handling in cholestatic liver disease: Effect of ursodeoxycholic acid treatment. Gastroenterology 1994; 106: 134-42.
96. 96 Stiehl A, Rudolph G, Sauer P, Theilmann L. Biliary secretion of bile acids and lipids in primary sclerosing cholangitis. Influence of cholestasis and effect of ursodeoxycholic acid treatment. J Hepatol 1995; 23: 283-9.
97. 97 Beuers U, Spengler U, Kruis W, et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a double blind, placebo-controlled trial. Hepatology 1992; 16: 707-14.
98. 98 Heathcote EJ, Cauch Dudek K, Walker V, et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19: 1149-56.
99. 99 Lindor KD, Dickson ER, Balsus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994; 106: 1284-90.
100. 100 Lindor KD. Ursodiol for primary sclerosing cholangitis. N Engl J Med 1997; 336: 691-5.
101. 101 Meng LJ, Reyes H, Palma J, Hernandez I, Ribalta J, Sjoevall J. Profiles of bile acids and progesterone metabolites in the urine and serum of women with intrahepatic cholestasis of pregnancy. J Hepatol 1997; 27: 346-57.
102. 102 Meng LJ, Reyes H, Paltna J, Hernandez I, Ribalta J, Sjoevall J. Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in scrum and urine of patients with intrahepatic cholestasis of pregnancy. J Hepatol 1997; 27: 1029-40.
103. 103 Brites D, Rodrigues CMP, Oliveira N, da Canceicao Cardoso M, Graca LM. Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy. J Hepatol 1998; 28: 91-8.
104. 2+ signals in isolated rat hepatocytes. Gastroenterology 1993; 104: 604-12.
105. 105 Beuers U, Nathanson MH, Isales CM, Boyer JL. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest 1993; 92: 2984-93.
106. 106 Beuers U, Throckmorton DC, Anderson MS, et al. Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology 1996; 110: 1553-63.
107. 107 Boyer JL, Soroka CJ. Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets. Gastroenterology 1995; 109: 1600-11.
108. 108 Kubitz R, D'Urso D, Kepler D, Häussinger D. Osmodependent dynamic localization of the multidrug resistance protein 2 in the rat hepatocyte canalicular membrane. Gastroenterology 1997; 113: 1438-42.
109. 109 Häussinger D, Saha N, Hallbrucker C, Lang F, Gerok W. Involvement of microtubules in the swelling-induced stimulation of taurocholate in perfused rat liver. Biochem J 1993; 291: 355-60.
110. 110 Schliess F, Kurz AK, vom Dahl S, Häussinger D. Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver. Gastroenterology 1997; 113: 1306-14.
111. 111 Prieto J, Qian C, Garcia N, Diez J, Medina JF. Abnormal expression of anion exchanger genes in primary biliary cirrhosis. Gastroenterology 1993; 105: 572-8.
112. 112 Medina JF, Martinez-Anso E, Vazquez JJ, Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 1997; 25: 12-17.
113. 113 Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339: 1217-27.
114. 114 Dumont M, Erlinger S, Uchman S. Hypercholeresis induced by ursodeoxycholic acid and 7-ketolithocholic acid in the rat: possible role of bicarbonate transport. Gastroenterology 1980; 79: 82-9.
115. 115 Yoon YB, Hagey LR, Hofmann AF, Gurantz D, Michelotti EL, Steinbach JH. Effect of side chain shortening on the physiological properties of bile acids: Hepatic transport and effect on biliary excretion of 23-norursodeoxycholate in rodents. Gastroenterology 1986; 90: 837-52.
116. + exchange in the rat is associated with decreased ursodeoxycholate hypercholeresis, decreased secretion of unconjugated ursodeoxycholate, and increased ursodeoxycholate glucuronidation. Gastroenterology 1988; 95: 454-63.
117. 117 Gurantz D, Schteingart CD, Hagey LR, Steinbach JH, Grotmol T, Hofmann AF. Hypercholeresis induced by unconjugated bile acid infusion correlates with recovery in bile of unconjugated bile acids. Hepatology 1991; 13: 540-50.
118. 118 Nakagawa M, Colombo C, Setchelt KDR. Comprehensive study of the biliary bile acid composition of patients with cystic fibrosis and associated liver disease before and after ursodeoxycholic acid administration. Hepatology 1990; 12: 322-34.
119. 119 Knyrim K, Vakil N, Pfab R, Classen M. The effects of intraduodenal bile acid administration on biliary secretion of ionized calcium and carbonate in man. Hepatology 1989; 10: 134-42.
120. 120 Oda M, Yokomori H, Ishii K, et al. Ursodeoxycholic acid enhances bile canalicular contractions. Hepatology 1990; 12: A999(Abstract).
121. 121 Phillips MJ, Poucell S, Oda M, Biology of disease. Mechanisms of cholestasis. Lab Invest 1986; 54: 593-608.
122. - currents in a biliary cell line. Gastroenterology 1995; 109: 965-72.
123. - currents in a human biliary cell line. In: Paumgartner G, Stiehl A, Gerok W, eds, Bile Acids in Hepatobiliary Diseases. Lancaster: Kluwer Academic Publishers, 1997: 219-23.
124. 124 Güldütuna S, Leuschner U, Imhof M, et al. Treatment of chronic active hepatitis and primary biliary cirrhosis with Ursodeoxycholic add. Gastroenterology 1992; 30: 49-54.
125. 125 Osuga T, Tanaka N, Matsuzaki Y, et al. Effect of Ursodeoxycholic acid in chronic active hepatitis and primary biliary cirrhosis. Dig Dis Sci 1989; 34: S49-51.
126. 126 Battezzati PM, Podda M, Bianchi FB, et al. Ursodeoxycholic acid for symptomatic primary biliary cirrhosis: Preliminary analysis of a double-blind multicenter trial. J Hepatol 1993; 17: 332-8.
127. 127 Batts KP, Jorgensen RA, Dickson ER, Lindor KD. Effects of Ursodeoxycholic acid on hepatic inflammation and histologic stage in patients with primary biliary cirrhosis. Am J Gastroenterol 1996; 91: 2314-17.
128. 128 Eriksson LS, Olsson R, Glauman H, et al. Ursodeoxycholic acid treatment in patients with primary biliary cirrhosis. A Swedish multicentre, double-blind, randomized controlled study, Scand J Gastroenterol 1997; 32: 179-86.
129. 129 Ludwig J, Dickson ER, McDonald, GSA. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Pathol Anat 1978; 379: 103-12.
130. 130 Poupon RE, Poupon R, Balkau B and the UDCA-PBC Study Group. Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 1994; 330: 1342-7.
131. 131 Lindor KD, Thernau TM. Jorgensen RA, Malinchoc M, Dickson ER. Effects of Ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology 1996; 110: 1515-18.
132. 132 Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of Ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997; 113: 884-90.
133. 133 Bonnand AM, Heathcote EJ, Lindor KD, Poupon RE. Clinical significance of serum bilirubin levels under Ursodeoxycholic acid therapy in patients with primary biliary cirrhosis. Hepatology 1999; 29: 39-43.
134. 134 Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER. Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis. Mayo Clin Proc 1997; 72: 1137-40.
135. 135 Huet PM, Huet J, Deslauriers J. Portal hypertension in patients with primary biliary cirrhosis. In: Lindor KD, Heathcote EJ, Poupon R, eds. Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment. Dordrecht: Kluwer Academic Publishers, 1998: 87-91.
136. 136 Pasha T, Heathcote J, Gabriel S, et al. Cost-effectiveness of ursodeoxycholic acid therapy in primary biliary cirrhosis. Hepatology 1999; 29: 21-6.
137. 137 Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: Clinical features and response to therapy. Hepatology 1998; 28: 296-301.
138. 138 Poupon RE, Huet PM, Poupon R, van Bonnand AM, Nhieu JT, Zafani ES and the UDCA-PBC Study Group. A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1996; 24: 1098-103.
139. 139 Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U, Ursodeoxycholic acid and prednisone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol 1996; 25: 49-57.
140. 140 Lindor KD, Dickson ER, Jorgensen RA, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: The results of a pilot study, Hepatology 1995; 22: 1158-62.
141. 141 Gonzalez-Koch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol 1997; 27: 143-9.
142. 142 Wolfhagen FHJ, Hoogstraten HJF, Buuren HR, et al. Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study. J Hepatol 1998; 29: 736-42.
143. 143 Chazouilleres O, Poupon R, Capron JP, et al. Ursodeoxycholic acid for primary sclerosing cholangitis. J Hepatol 1990; 11: 120-3.
144. 144 O'Brien CB, Senior JR, Arora-Mirchandani R, Batta AK, Salen G. Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study. Hepatology 1991; 14: 838-47.
145. 145 Stiehl A, Walker S, Stiehl L, Rudolph G, Hofmann WJ, Theilmann L. Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period. J Hepatol 1994; 20: 57-64.
146. 146 Stiehl A, Rudolph G, Sauer P, et al. Efficacy of ursodeoxycholic acid treatment and endoscopic dilatation of major duct stenoses in primary sclerosing cholangilis. J Hepatol 1997; 26: 560-6.
147. 147 van Hoogstraten HJF, Wolfhagen FHJ, van de Meeberg PC, et al. Ursodeoxycholic acid therapy tor primary sclerosing cholangitis: Results of a 2-year randomized controlled trial to evaluate single versus multiple doses. J Hepatol 1998; 29: 417-23.
148. 148 Palma J, Reyes H, Ribalta J, et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992; 15: 1043-7.
149. 149 Marpeau L, Chazouillien D, Rhimi Z, Poupon R, Pigne A, Barrat J. Pregnancy-associated idiopathic intrahepatic cholestasis. Hypothesis of physiopathology: a therapeutic case report. Fetal Diagn Ther 1991; 6: 120-5.
150. 150 Mazella G, Rizzo N, Salzetta A, Iampieri R, Bovicelli L, Roda E, Management of intrahepatic cholestasis in pregnancy. Lancet 1991; 338: 1594-5.
151. 151 Brites D, Poeiras J, Rodrigues C. Intrahepatic cholestasis of pregnancy. Etiopathogenesis, prognosis and treatment. Acta Med Port 1994; 7: 181-8.
152. 152 Davies MH, da Silva RCMA, Jones SR, Weaver JB, Elias E. Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid, Gut 1995; 37: 580-4.
153. 153 Palma J, Reyes H, Ribalta J. et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol 1997; 27: 1022-8.
154. 154 Meng LJ, Reyes H, Axelson M, et al. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy. Hepatology 1997; 26: 1573-9.
155. 155 Fried RH, Murakami CS, Fisher LD, Wilsson RA, Sullivan KM, McDonald GB. Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver. Ann Intern Med 1992; 116: 624-9.
156. 156 Wulffrat NM, Haddad E, Benkerrou M, et al. Hepatic GvHD after HLA-haploidentical bone marrow transplantation in children with severe combined immunodeficiency: The effect of ursodeoxycholic acid. Br J Haematol 1997; 96: 776-80.
157. 157 Essell JH, Schröder MT, Harman GS, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized double-blind, placebo-controlled trial. Ann Intern Med 1998; 128: 975-81.
158. 158 Whitington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatology 1985; 5: 693-6.
159. 159 Lindor KD, Burnes J, Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis. A case report. Gastroenterology 1991; 101: 250-3.
160. 160 Spagnuolo MA, Iorio R, Vegnente A. Guarino A. Ursodeoxycholic acid for the treatment of cholestasis in children on long-term total parenteral nutrition: a pilot study. Gastroenterology 1996; 111: 716-19.
161. 161 Kallinowski B, Theilmann L, Zimmermann R, Gams E, Kommerell B, Stiehl A. Effective treatment of cyclosporine-induced cholestasis in heart-transplanted patients treated with ursodeoxycholic acid. Transplantation 1991; 51: 1128-9.
162. 162 Mallat A, Zafrani ES, Metreau JM, Dhumcaux D. Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts. Dig Dis Sci 1997; 42: 1486-8.
163. 163 Alam I, Ferrell LD, Bass NM. Vanishing bile duct syndrome temporally associated with ibuprofen use. Am J Gastroenterol 1996; 91: 1626-30.
164. 164 Moradpour D, Altorfer J, Flury R, et al. Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology 1994; 20: 1437-41.
165. 165 Feigelson J, Anagnostopoulos C, Poquet M, Pecau Y, Munck A, Navarro J. Liver cirrhosis in cystic fibrosis - therapeutic implications and long term follow-up. Arch Dis Child 1993; 68: 653-7.
166. 166 Cotting J, Lentze MJ, Reichen J. Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis. Gut 1990; 31: 918-21.
167. 167 Colombo C, Crosignani A, Assaisso M, et al. Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose response study. Hepatology 1992; 16: 924-30.
168. 168 Colombo C, Battezzati PM, Podda M, Bettinardi N, Giunta A. Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis. Hepatology 1996; 23: 1484-90.
169. 169 Lindblad A, Glaumann H, Houwen B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease, Hepatology 1998; 27: 166-74.
170. 170 van de Meeberg PC, Houwen RH, Sinaasappel M, Heijerman HG, van Bijleveld CM, Berge Henegouwen GP. Low-dose versus high-dose ursodeoxycholic acid in cystic fibrosis-related cholestatic liver disease. Results of a randomized study with 1-year follow-up. Scand J Gastroenterol 1997; 32: 269-373.
171. 171 Nittono H, Tokita A, Hayashi M, et al. Ursodeoxycholic acid therapy in the treatment of biliary atresia. Biomed Pharmacother 1989; 43: 37-41.
172. 172 Ullrich D, Rating D, Schröter W, Hanefeld F, Bircher J. Treatment with ursodeoxycholic acid renders children with biliary atresia suitable for liver transplantation. Lancet 1987; 2: 1324.
173. 173 Balestreri WF, Setchell KD, Ryckman FC and the UDCA Study Group. Bile acid therapy in pedriatic liver disease. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile Acids and the Hepatobiliary System. London: Kluwer Academic Publishers, 1993: 271-82.
174. 174 Ros E, Navarro S, Bru C, Gilabert R, Bianchi L, Bruguera M. Ursodeoxycholic acid treatment of primary hepatolithiasis in Caroli's syndrome. Lancet 1993; 342: 404-6.
175. 175 Maggiore G, de Giacomo C. Efficacy of ursodeoxycholic acid in preventing cholestatic episodes in a patient with benign recurrent intrahepatic cholestasis. Hepatology 1992; 16: 504.
176. 176 Persson H, Friman S, Schersten T, Svanvik J, Karlberg I. Ursodeoxycholic acid for prevention of acute rejection in liver transplant recipients. Lancet 1990; 336: 52-3.
177. 177 Friman S, Persson H, Schersten T, Svanik J, Karlberg I. Adjuvant treatment with ursodeoxycholic acid reduces acute rejection after liver transplantation. Transplant Proc 1992; 24: 389-90.
178. 178 Pageaux GP, Blanc P, Perrigault PF, et al. Failure of ursodeoxycholic acid to prevent acute cellular rejection after liver transplantation. J Hepatol 1995; 23: 119-22.
179. 179 Keiding S, Höckerstedt K, Bjoro K, et al. The Nordic multicenter double-blind randomized controlled trial of prophylactic ursodeoxycholic acid in liver transplant patients. Transplantation 1997; 63: 1591-4.
180. 180 Barnes D, Talenti D, Cammell G, et al. A randomized clinical trial of ursodeoxycholic acid as adjuvant treatment to prevent liver transplant rejection. Hepatology 1997; 26: 853-7.
181. 181 Fleckenstein JF, Paredes M, Thuluvath PJ. A prospective, randomized, double-blind trial evaluating the efficacy of ursodeoxycholic acid in prevention of liver transplant rejection. Liver Transpl Surg 1998; 4: 276-9.
182. 182 Boucher E, Jouanolle H, Andre P, et al. Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: Results from a controlled randomized trial in 80 patients. Hepatology 1995; 21: 322-7.
183. 183 Angelico M, Gandin C, Pescarmona E, et al. Recombinant interferon-alpha and ursodeoxycholic acid versus interferon-alpha alone in the treatment of chronic hepatitis C. A randomized clinical trial with long-term follow-up. Am J Gastroenterol 1995; 90: 263-9.
184. 184 Bellentani S, Podda M, Tiribelli C, et al. Ursodiol in the long-term treatment of chronic hepatitis: a double-blind multicenter clinical trial. J Hepatol 1993; 19: 459-64.
185. 185 Bonkovsky HL. Therapy of hepatitis C: Other options. Hepatology 1997; 26(Suppl.1): S143-51.
186. 186 Kiso S, Kawara S, Imai Y, et al. Efficacy of ursodeoxycholic acid therapy in chronic viral hepatitis C with high gamma-glutamyltranspeptidase. J Gastroenterol 1996; 31: 75-80.
187. 187 Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-7.
188. 188 Plevris JN, Hayes PC, Bouchier IAD. Ursodeoxycholic acid in the treatment of alcoholic liver disease. Eur J Gastroenterol Hepatol 1991; 3: 653-6.