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Gastroenterologie
a hepatologie

Gastroenterology and Hepatology

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MOLECULAR BASIS FOR RATIONAL CLINICAL USE OF URSODEOXYCHOLIC ACID – RECENT DEVELOPMENTS



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Ursodeoxycholic acid (UDCA) is increasingly used for the treatment of cholestatic disorders(1-3). In primary biliary cirrhosis, UDCA (13–15 mg/kg/d) improves serum liver tests, delays progression to severe fibrosis or cirrhosis(4) and may prolong transplant-free survival(5). In primary sclerosing cholangitis, UDCA (ł 15 mg/kg/d) improves serum liver tests and surrogate markers of prognosis. Anticholestatic effects of UDCA have also been observed in intrahepatic cholestasis of pregnancy, chronic graft-versus host disease, drug- and parenteral nutrition-induced cholestasis, liver disease of cystic fibrosis, and pediatric cholestatic syndromes such as progressive familial intrahepatic cholestasis (reviewed in 1–3).

Experimental evidence suggests three major mechanisms of action:

1. Stimulation of biliary secretion by UDCA is mediated by intracellular signalling via [Ca++]i and protein kinase C or activation of p38MAPK and extracellular signal regulated kinases (Erk) in hepatocytes which result in insertion of transporter molecules such as the conjugate (Mrp2) and bile salt (Bsep) export pumps into apical membranes of hepatocytes and improved biliary secretion of bile acids and many other cholephiles(6-10). Secretion of chloride and bicarbonate by cholangiocytes is also stimulated by UDCA in cholestatic patients and experimental models.

2. Protection of hepatocytes against bile acid-induced apoptosis by UDCA is associated with a reduction of mitochondrial membrane permeability transition (MMPT) which is enhanced in hepatocytes by a number of apoptotic stimuli including hydrophobic bile acids. In addition, activation of the epidermal growth factor receptor by UDCA may contribute to its antiapoptotic effect(11-13).

3. Protection of cholangiocytes by UDCA against cytotoxicity of hydrophobic bile acids may be caused by modulation of the composition of mixed phospholipid-rich micelles in bile rather than direct membrane interactions(14).

It remains unclear to which degree these different mechanisms and sites of action of UDCA may contribute to the anticholestatic effect of UDCA at the molecular level.

References

1. PAUMGARTNER, G., BEUERS, U. Clin Liver Dis, 2004, 8, p. 67–81.

2. LAZARIDIS, KN., GORES, GJ., LINDOR, KD. J Hepatol, 2001, 35, 134–46.

3. BEUERS, U., BOYER, JL., PAUMGARTNER, G. Hepatology, 1998, 28, p. 1449–1453.

4. CORPECHOT, C., CARRAT, F., BONNAND, AM., et al. Hepatology, 2000, 32, p. 1196–1199.

5. POUPON, RE., LINDOR, KD., CAUCH-DUDEK, K., et al. Gastroenterology, 1997, 113, p. 884–890.

6. BEUERS, U., NATHANSON, MH., ISALES, C., et al. J Clin Invest 1993;92:2984-2993.

7. BEUERS, U., BILZER, M., CHITTATTU, A., et al. Hepatology 2001;33:1206-1216.

8. SCHLIESS, F., KURZ, AK., VOM DAHL, S., HAUSSINGER, D. Gastroenterology, 1997, 113, p. 1306–1314.

9. KURZ, AK., GRAF, D., SCHMITT, M., et al. Gastroenterology, 2001, 121, p. 407–419.

10. HÄUSSINGER, D., KURZ, AK., WETTSTEIN, M., et al. Gastroenterology, 2003, 124, p. 1476–1487.

11. BENZ, C., ANGERMÜLLER, S., TÖX, U., et al. J Hepatol, 1998, 28, p. 99–106.

12. RODRIGUEZ, CMP., FAN, G., MA, X., et al. J Clin Invest, 1998, 101, p. 2790–2799.

13. QIAO, L., YACOUB, A., STUDER, E., et al. Hepatology, 2002, 35, p. 779–789.

14. HEUMAN, DM., BAJAJ, RS., LIN, Q. J Lipid Res, 1996, 37, p.562–573.

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