Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fickert, P; Pollheimer, MJ; Silbert, D; Moustafa, T; Halilbasic, E; Krones, E; Durchschein, F; Thüringer, A; Zollner, G; Denk, H; Trauner, M.
Differential effects of norUDCA and UDCA in obstructive cholestasis in mice.
J Hepatol. 2013; 58(6):1201-1208
Doi: 10.1016/j.jhep.2013.01.026
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- Führende Autor*innen der Med Uni Graz
- Fickert Peter
- Pollheimer Marion
- Trauner Michael
- Co-Autor*innen der Med Uni Graz
- Baumann-Durchschein Franziska
- Denk Helmut
- Halilbasic Emina
- Moustafa Tarek
- Silbert-Wagner Dagmar
- Tatscher Elisabeth
- Zollner Gernot
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- Abstract:
- 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. 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. 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. 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 profound differences in metabolism and therapeutic mechanisms of both bile acids with important clinical consequences. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenosine Triphosphate - metabolism
- Animals -
- Bicarbonates - metabolism
- Cholestasis - drug therapy Cholestasis - metabolism Cholestasis - pathology
- Humans -
- Male -
- Mice -
- Mice, Inbred C57BL -
- Ursodeoxycholic Acid - analogs & derivatives Ursodeoxycholic Acid - therapeutic use
- Find related publications in this database (Keywords)
- 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