Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

  title={Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited},
  author={Gustav Paumgartner and Ulrich Beuers},
Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid‐rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary… 

Ursodeoxycholic acid for primary biliary cirrhosis: treat early to slow progression.

The Therapeutic Role of Ursodeoxycholic Acid in Digestive Diseases

Several potential uses of UDCA warrant further investigation after initial studies have shown promise including treatment for microlithiasis, intrahepatic cholestasis of pregnancy, total parenteral nutrition, chemoprophylaxis of colorectal cancer in patients with ulcerative colitis and PSC, viral hepatitis, and in bone marrow transplantation.

Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease.

Immunomodulating and anti-apoptotic action of ursodeoxycholic acid: where are we and where should we go?

  • S. Bellentani
  • Biology, Medicine
    European journal of gastroenterology & hepatology
  • 2005
In this issue of the journal, Weitzel and co-workers clearly demonstrated that the binding of UDCA to the glucocorticoid receptor is unspecific, and the anti-inflammatory, cytoprotective and anti-apoptotic actions ofUDCA should be due not only to the mild interaction with the glucose receptor, but also to transactivation or transrepression of different cytoplasmic proteins that are involved in the survival pathway.

Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in the abcb11-/- mouse: transport and gene expression studies.

  • Renxue WangLin Liu V. Ling
  • Biology, Medicine
    American journal of physiology. Gastrointestinal and liver physiology
  • 2013
It was concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11-/- mice, and Semiquantitative RT-PCR showed that genes encoding Mdr 1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abCB11- +/- mice.

Ursodeoxycholic acid in cholestatic liver diseases : current status

  • Medicine
  • 2011
The US and European hepatological societies found sufficient data to recommend UDCA as the drug of choice in primary biliary cirrhosis and intrahepatic cholestasis of pregnancy and UDCA is also accepted for the treatment of selected cases of cholelithiasis.

Bile Acid Receptors and Bile Acid Signaling as Therapeutic Targets

The discovery of the presence of biles acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases.



Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver.

Down-regulation of basolateral and up- regulation of canalicular transporters in response to CA may represent a defense mechanism, in an attempt to prevent hepatocellular accumulation of potentially toxic bile acids.

Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene.

The cholangiolitis and its sequelae in the mdr2 knockout mice depend on bile salt hydrophobicity.

Ursodeoxycholic Acid May Inhibit Deoxycholic Acid-Induced Apoptosis by Modulating Mitochondrial Transmembrane Potential and Reactive Oxygen Species Production

UDCA significantly reduces DCA-induced disruption of ΔΨm, ROS production, and Bax protein abundance in mitochondria, suggesting both short- and long-term mechanisms in preventing MPT.

Pharmacology of ursodeoxycholic acid, an enterohepatic drug.

  • A. Hofmann
  • Biology, Medicine
    Scandinavian journal of gastroenterology. Supplement
  • 1994
Ursodeoxycholic acid is a choleretic agent, as all bile acids, but differs from other dihydroxy-bile acids in being non-cytotoxic because it has less affinity for membranes, and when present at micellar concentrations does not solubilize membranes.

Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha

In conclusion, activation of Ca2+‐dependent PKC alpha is required for UDCA and TUDCA inhibition of cholangiocyte growth and secretion.

Ursodeoxycholic acid in cholestasis: Potential mechanisms of action and therapeutic applications

Clinical and experimental work that may help to clarify possible mechanisms of action of UDCA in cholestasis and provide a clearer rationale for the administration ofUDCA in special cholESTatic disorders are summarized.

Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes.

TUDCA might stimulate Ca(2+)-dependent hepatocellular exocytosis into bile in part by activation of alpha-PKC.

Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats.

TUDC-induced stimulation of canalicular TC excretion involves a MAP kinase-dependent translocation of subcanalicular Bsep to the canalicular membrane and dual activation of Erks and p38(MAPK) is required for the choleretic effect of both TUDC and hypo-osmotic cell swelling.