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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

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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.

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

    Ulrich Beuers

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Correspondence to Ulrich Beuers.

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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.

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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

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