Differential effects of norUDCA and UDCA in obstructive cholestasis in mice

JOURNAL OF HEPATOLOGY

卷:58

Article

Fickert, Peter^1,2  Pollheimer, Marion J.^1,2  Silbert, Dagmar¹  Moustafa, Tarek¹  Halilbasic, Emina³  Krones, Elisabeth¹  Durchschein, Franziska¹  Thueringer, Andrea²  Zollner, Gernot¹  Denk, Helmut²  Trauner, Michael³ 

[1] Med Univ Graz, Div Gastroenterol & Hepatol, Dept Internal Med, Lab Expt & Mol Hepatol, A-8036 Graz, Austria

[2] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[3] Med Univ Vienna, Div Gastroenterol & Hepatol, Hans Popper Lab Mol Hepatol, Dept Internal Med 3, Vienna, Austria

关键词: Bile acids;    Bile infarcts;    Biliary pressure;    Bile duct epithelial cells;    Cholestasis;    Cholestatic liver injury;    Cholangiopathy;    Hepatic transport;    Liver injury;    Obstructive jaundice;    norUDCA;    UDCA;    Main bile duct stricture;    Primary sclerosing cholangitis;   

DOI  :  10.1016/j.jhep.2013.01.026

来源: Elsevier

【 摘 要 】

Background & Aims: The quest for effective drugs to treat cholangiopathies led to the development of norUDCA previously shown to have potent choleretic effects and to heal cholangiopathy in Abcb4 knockout (Abcb4(-/-)) mice. Its mother compound UDCA had detrimental effects in common bile duct ligated (CBDL) mice, presumably related to its choleretic effects. norUDCA choleretic effects may therefore raise safety concerns when used in cholangiopathies with biliary obstruction. We therefore aimed at comparing the effects of UDCA and norUDCA in clear-cut obstructive cholestasis. Methods: 0.5% UDCA- or norUDCA-fed wild type and Abcb4(-/-) mice were subjected to CBDL or selective bile duct ligation (SBDL) and compared to controls with regard to liver injury. Bile flow, bile composition, and biliary manometry were compared in UDCA-fed, norUDCA-fed and control mice. Toxicity of UDCA and norUDCA was compared in vitro. Results: Compared to UDCA, liver injury in CBDL mice was significantly lower in almost all norUDCA groups. In SBDL mice, only UDCA induced bile infarcts in the ligated lobes, whereas norUDCA even ameliorated liver injury. In vitro, UDCA induced cellular ATP depletion and was significantly more toxic than norUDCA in HepG2 cells, mouse bile duct epithelial cells, and primary human hepatocytes. Conclusions: Compared to norUDCA, UDCA is significantly more toxic in CBDL mice. norUDCA, in contrast to UDCA, significantly ameliorates liver injury in SBDL mice. Our findings uncover pro-found differences in metabolism and therapeutic mechanisms of both bile acids with important clinical consequences. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free