Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drug Insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis

Nature Clinical Practice Gastroenterology & Hepatology volume 3, pages 318–328 (2006)Cite this article

Abstract

Ursodeoxycholic acid (UDCA) exerts anticholestatic effects in various cholestatic disorders. Several potential mechanisms and sites of action of UDCA have been unraveled in clinical and experimental studies, which could explain its beneficial effects. The relative contribution of these mechanisms to the anticholestatic action of UDCA depends on the type and stage of the cholestatic injury. In early-stage primary biliary cirrhosis and primary sclerosing cholangitis, protection of injured cholangiocytes against the toxic effects of bile acids might prevail. Stimulation of impaired hepatocellular secretion by mainly post-transcriptional mechanisms, including stimulation of synthesis, targeting and apical membrane insertion of key transporters, seems to be relevant in more advanced cholestasis. In intrahepatic cholestasis of pregnancy, stimulation of impaired hepatocellular secretion could be crucial for rapid relief of pruritus and improvement of serum liver tests, as it is in some forms of drug-induced cholestasis. In cystic fibrosis, stimulation of cholangiocellular calcium-dependent secretion of chloride and bicarbonate ions could have a major impact. Inhibition of bile-acid-induced hepatocyte apoptosis can have a role in all states of cholestasis that are characterized by hepatocellular bile-acid retention. Different mechanisms of action could, therefore, contribute to the beneficial effect of UDCA under various cholestatic conditions.

Key Points

  • Ursodeoxycholic acid (UDCA) exerts its beneficial effects in various cholestatic disorders mainly at the level of hepatocytes and cholangiocytes

  • UDCA stimulates impaired hepatocyte secretion by mostly post-transcriptional mechanisms, which include enhanced synthesis, targeting and membrane insertion of transporters

  • UDCA exerts antiapoptotic effects in hepatocytes at the level of the mitochondria

  • UDCA might protect cholangiocytes against the toxic effects of endogenous bile acids by rendering bile less toxic and modifying micelle formation, rather than by direct membrane effects

  • UDCA might stimulate impaired cholangiocellular secretion of chloride and bicarbonate anions, by transcriptional and post-transcriptional mechanisms

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A chromatogram of bile acids in the bile of the Chinese black bear.
Figure 2: Experimental animal models of post-transcriptional regulation of hepatocellular apical secretion by ursodeoxycholic acid conjugates, in normal and cholestatic liver cells.
Figure 3: Modulation of hepatocyte apoptosis by bile acids, as proposed on the basis of experimental studies.
Figure 4: Modulation of cholangiocyte secretion by ursodeoxycholic acid conjugates as proposed on the basis of experimental studies.
Figure 5: Potential mechanisms and sites of action of ursodeoxycholic acid in cholestatic liver disease.

Similar content being viewed by others

References

  1. Hofmann AF (1994) Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol Suppl 204: 1–15

    Article  CAS  PubMed  Google Scholar 

  2. Leuschner U et al. (1985) Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 30: 642–649

    Article  CAS  PubMed  Google Scholar 

  3. Poupon R et al. (1987) Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1: 834–836

    Article  CAS  PubMed  Google Scholar 

  4. Paumgartner G and Beuers U (2004) Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis 8: 67–81

    Article  PubMed  Google Scholar 

  5. Lazaridis KN et al. (2001) Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. J Hepatol 35: 134–146

    Article  CAS  PubMed  Google Scholar 

  6. Poupon R and Poupon RE (2000) Treatment of primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol 14: 615–628

    Article  CAS  PubMed  Google Scholar 

  7. Goulis J et al. (1999) Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 354: 1053–1060

    Article  CAS  PubMed  Google Scholar 

  8. Gluud C and Christensen E (2002) Ursodeoxycholic acid for primary biliary cirrhosis. The Cochrane Database of Systematic Reviews, Issue 4, Art. No CD000551

    Google Scholar 

  9. Poupon RE (2000) Ursodeoxycholic acid for primary biliary cirrhosis: lessons from the past—issues for the future. J Hepatol 32: 685–688

    Article  CAS  PubMed  Google Scholar 

  10. Palma J et al. (1997) Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol 27: 1022–1028

    Article  CAS  PubMed  Google Scholar 

  11. Glantz A et al. (2005) Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 42: 1399–1405

    Article  CAS  PubMed  Google Scholar 

  12. Kondrackiene J et al. (2005) Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 129: 894–901

    Article  CAS  PubMed  Google Scholar 

  13. Trauner M and Boyer JL (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83: 633–671

    Article  CAS  PubMed  Google Scholar 

  14. Sauer P et al. (1999) Influence of cholestasis on absorption of ursodeoxycholic acid. Dig Dis Sci 44: 817–822

    Article  CAS  PubMed  Google Scholar 

  15. Hruz P et al. (2006) Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis. Gut 55: 395–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jazrawi RP et al. (1994) Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid. Gastroenterology 106: 134–142

    Article  CAS  PubMed  Google Scholar 

  17. Medina JF et al. (1997) Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 25: 12–17

    Article  CAS  PubMed  Google Scholar 

  18. Fickert P et al. (2001) Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology 121: 170–183

    Article  CAS  PubMed  Google Scholar 

  19. Marschall HU et al. (2005) Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129: 476–485

    Article  PubMed  Google Scholar 

  20. Beuers U et al. (2001) Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 33: 1206–1216

    Article  CAS  PubMed  Google Scholar 

  21. Kurz AK et al. (2001) Tauroursodesoxycholate-induced choleresis involves p38 (MAPK) activation and translocation of the bile salt export pump in rats. Gastroenterology 121: 407–419

    Article  CAS  PubMed  Google Scholar 

  22. Dombrowski F et al. (2006) Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab Invest 86: 166–174

    Article  CAS  PubMed  Google Scholar 

  23. Kubitz R et al. (2004) Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology 126: 541–553

    Article  CAS  PubMed  Google Scholar 

  24. Crawford JM (1996) Role of vesicle-mediated transport pathways in hepatocellular bile secretion. Semin Liver Dis 16: 169–189

    Article  CAS  PubMed  Google Scholar 

  25. Kubitz R et al. (2005) Biliary transport systems: short-term regulation. Methods Enzymol 400: 542–557

    Article  CAS  PubMed  Google Scholar 

  26. Beuers U et al. (1993) Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca2+ mechanisms defective in cholestasis. J Clin Invest 92: 2984–2993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beuers U et al. (1993) Effects of tauroursodeoxycholic acid on cytosolic Ca2+ signals in isolated rat hepatocytes. Gastroenterology 104: 604–612

    Article  CAS  PubMed  Google Scholar 

  28. Bouscarel B et al. (1993) Ursodeoxycholate mobilizes intracellular Ca2+ and activates phosphorylase a in isolated hepatocytes. Am J Physiol 264 (Pt 1): G243–G251

    CAS  PubMed  Google Scholar 

  29. Beuers U et al. (1996) Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology 110: 1553–1563

    Article  CAS  PubMed  Google Scholar 

  30. Stravitz RT et al. (1996) Hepatocellular protein kinase C activation by bile acids: implications for regulation of cholesterol 7 alpha-hydroxylase. Am J Physiol 271 (Pt 1): G293–G303

    CAS  PubMed  Google Scholar 

  31. Bouscarel B et al. (1995) Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: a role for PKC. Am J Physiol 268 (Pt 1): G300–G310

    CAS  PubMed  Google Scholar 

  32. Bouscarel B et al. (1999) Signal transduction and hepatocellular bile acid transport: cross talk between bile acids and second messengers. Gastroenterology 117: 433–452

    Article  CAS  PubMed  Google Scholar 

  33. Milkiewicz P et al. (2002) Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways. Gut 51: 113–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Beuers U et al. (1998) Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology 28: 1449–1453

    Article  CAS  PubMed  Google Scholar 

  35. Kubitz R et al. (2004) Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver. J Biol Chem 279: 10323–10330

    Article  CAS  PubMed  Google Scholar 

  36. Beuers U et al. (1999) Modulation of protein kinase C by taurolithocholic acid in isolated rat hepatocytes. Hepatology 29: 477–482

    Article  CAS  PubMed  Google Scholar 

  37. Beuers U et al. (2003) Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol 3-kinase-dependent mechanisms in perfused rat livers and rat hepatocyte couplets. J Biol Chem 278: 17810–17818

    Article  CAS  PubMed  Google Scholar 

  38. Haussinger D et al. (2003) Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis. Gastroenterology 124: 1476–1487

    Article  PubMed  CAS  Google Scholar 

  39. Schliess F et al. (1997) Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver. Gastroenterology 113: 1306–1314

    Article  CAS  PubMed  Google Scholar 

  40. Stiehl A et al. (1995) Biliary secretion of bile acids and lipids in primary sclerosing cholangitis. Influence of cholestasis and effect of ursodeoxycholic acid treatment. J Hepatol 23: 283–289

    CAS  PubMed  Google Scholar 

  41. Boyer JL et al. Up-regulation of a basolateral FXR-dependent bile acid efflux transporter, OSTα–OSTβ, in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol, in press

  42. Noe J et al. (2001) Characterization of the mouse bile salt export pump overexpressed in the baculovirus system. Hepatology 33: 1223–1231

    Article  CAS  PubMed  Google Scholar 

  43. Faubion W et al. (1999) Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 103: 137–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Reinehr R et al. (2003) Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation. Gastroenterology 125: 839–853

    Article  CAS  PubMed  Google Scholar 

  45. Benz C et al. (1998) Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes. J Hepatol 28: 99–106

    Article  CAS  PubMed  Google Scholar 

  46. Rodrigues C et al. (1998) Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med 4: 165–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Benz C et al. (2000) Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes. Eur J Clin Invest 30: 203–209

    Article  CAS  PubMed  Google Scholar 

  48. Azzaroli F et al. (2002) Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. Hepatology 36: 49–54

    Article  CAS  PubMed  Google Scholar 

  49. Graf D et al. (2002) Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner. Gastroenterology 122: 1411–1427

    Article  CAS  PubMed  Google Scholar 

  50. Schoemaker MH et al. (2004) Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways. Hepatology 39: 1563–1573

    Article  CAS  PubMed  Google Scholar 

  51. Sola S et al. (2005) Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-β1-induced apoptosis in rat hepatocytes. Hepatology 42: 925–934

    Article  CAS  PubMed  Google Scholar 

  52. Fickert P et al. (2005) Oncosis represents the main type of cell death in mouse models of cholestasis. J Hepatol 42: 378–385

    Article  CAS  PubMed  Google Scholar 

  53. Guicciardi ME and Gores GJ (2005) Cholestatic hepatocellular injury: what do we know and how should we proceed? J Hepatol 42: 297–300

    Article  PubMed  Google Scholar 

  54. Paolini M et al. (1999) Bile acid structure and selective modulation of murine hepatic cytochrome P450-linked enzymes. Hepatology 30: 730–739

    Article  CAS  PubMed  Google Scholar 

  55. Schuetz EG et al. (2001) Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276: 39411–39418

    Article  CAS  PubMed  Google Scholar 

  56. Bodin K et al. (2001) Antiepileptic drugs increase plasma levels of 4β-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J Biol Chem 276: 38685–38689

    Article  CAS  PubMed  Google Scholar 

  57. Dilger K et al. (2005) No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology 41: 595–602

    Article  CAS  PubMed  Google Scholar 

  58. Calmus Y et al. (1990) Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology 11: 12–15

    Article  CAS  PubMed  Google Scholar 

  59. Tanaka H et al. (1996) Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway. J Immunol 156: 1601–1608

    CAS  PubMed  Google Scholar 

  60. Weitzel C et al. (2005) Ursodeoxycholic acid induced activation of the glucocorticoid receptor in primary rat hepatocytes. Eur J Gastroenterol Hepatol 17: 169–177

    Article  CAS  PubMed  Google Scholar 

  61. Hofmann AF (1999) Bile acids: the good, the bad, and the ugly. News Physiol Sci 14: 24–29

    CAS  PubMed  Google Scholar 

  62. Fickert P et al. (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127: 261–274

    Article  CAS  PubMed  Google Scholar 

  63. Heuman DM et al. (1996) Adsorption of mixtures of bile salt taurine conjugates to lecithin-cholesterol membranes: implications for bile salt toxicity and cytoprotection. J Lipid Res 37: 562–573

    CAS  PubMed  Google Scholar 

  64. Lindor KD et al. (1998) Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis. Am J Gastroenterol 93: 1498–1504

    Article  CAS  PubMed  Google Scholar 

  65. Rost D et al. (2004) Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology 40: 693–698

    Article  CAS  PubMed  Google Scholar 

  66. Van Nieuwkerk CM et al. (1996) Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology 111: 165–171

    Article  CAS  PubMed  Google Scholar 

  67. Fickert P et al. (2002) Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 123: 1238–1251

    Article  CAS  PubMed  Google Scholar 

  68. Alpini G et al. (2002) Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha. Hepatology 35: 1041–1052

    Article  CAS  PubMed  Google Scholar 

  69. Nathanson MH et al. (2001) Stimulation of ATP secretion in the liver by therapeutic bile acids. Biochem J 358: 1–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dranoff JA et al. (2001) Polarized expression and function of P2Y ATP receptors in rat bile duct epithelia. Am J Physiol Gastrointest Liver Physiol 281: G1059–G1067

    Article  CAS  PubMed  Google Scholar 

  71. Prieto J et al. (1999) Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology 117: 167–172

    Article  CAS  PubMed  Google Scholar 

  72. Marteau P et al. (1990) Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man. Hepatology 12: 1206–1208

    Article  CAS  PubMed  Google Scholar 

  73. Eusufzai S et al. (1991) Effect of ursodeoxycholic acid treatment on ileal absorption of bile acids in man as determined by the SeHCAT test. Gut 32: 1044–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Stiehl A et al. (1990) Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids. Gastroenterology 98: 424–428

    Article  CAS  PubMed  Google Scholar 

  75. Lanzini A et al. (2003) Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration. Gut 52: 1371–1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hofmann AF (2003) Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry. Gut 52: 1239–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Beuers U et al. (1992) Effect of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease. Hepatology 15: 603–608

    Article  CAS  PubMed  Google Scholar 

  78. Rudolph G et al. (1993) Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis. Hepatology 17: 1028–1032

    Article  CAS  PubMed  Google Scholar 

  79. Yoshikawa M et al. (1992). Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology 16: 358–364

    Article  CAS  PubMed  Google Scholar 

  80. Calmus Y et al. (1992) Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes. Hepatology 16: 719–723

    Article  CAS  PubMed  Google Scholar 

  81. Bergamini A et al. (1997) Bile acids with differing hydrophilic–hydrophobic properties do not influence cytokine production by human monocytes and murine Kupffer cells. Hepatology 25: 927–933

    Article  CAS  PubMed  Google Scholar 

  82. Poo JL et al. (1992) Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat. Gastroenterology 102: 1752–1759

    Article  CAS  PubMed  Google Scholar 

  83. Corpechot C et al. (2000) The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 32: 1196–1199

    Article  CAS  PubMed  Google Scholar 

  84. Beuers U et al. (1991) Formation of iso-ursodeoxycholic acid during administration of ursodeoxycholic acid in man. J Hepatol 13: 97–103

    Article  CAS  PubMed  Google Scholar 

  85. Rust C et al. (2000) The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3- kinase-dependent survival signaling cascade. J Biol Chem 275: 20210–20216

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Professor of Medicine in the Department of Medicine II, Klinikum Grosshadern, University of Munich, Germany

    Ulrich Beuers

Authors
  1. Ulrich Beuers
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Ulrich Beuers.

Ethics declarations

Competing interests

The author has received honoraria for lectures from The Falk Foundation. The author is/has been an investigator of clinical trials on the pharmacokinetics of budenoside in primary biliary cirrhosis, clinical efficacy of budenoside in autoimmune hepatitis and efficacy of UDCA in primary sclerosing cholangitis, which were supported by Dr Falk Pharma. The author did not receive any salary for his contributions to these trials.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beuers, U. Drug Insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Rev Gastroenterol Hepatol 3, 318–328 (2006). https://doi.org/10.1038/ncpgasthep0521

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpgasthep0521

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing