Differential effects of norUDCA and UDCA in obstructive cholestasis in mice.
OBJECTIVE
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 profound differences in metabolism and therapeutic mechanisms of both bile acids with important clinical consequences.
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria. peter.fickert@medunigraz.at
Peter
P
Fickert
Marion J
MJ
Pollheimer
Dagmar
D
Silbert
Tarek
T
Moustafa
Emina
E
Halilbasic
Elisabeth
E
Krones
Franziska
F
Durchschein
Andrea
A
Thüringer
Gernot
G
Zollner
Helmut
H
Denk
Michael
M
Trauner
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D001639:Bicarbonates; D014580:Ursodeoxycholic Acid; D000255:Adenosine Triphosphate; C081331:24-norursodeoxycholic acid