24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.
OBJECTIVE
Current therapy for primary sclerosing cholangitis is of limited efficacy. Multidrug resistance gene 2 knockout mice (Mdr2(-/-)) represent a well-characterized model for sclerosing cholangitis. Experiments were performed to test in such mice the therapeutic effects of 24-norUrsodeoxycholic acid, a C(23) homologue of ursodeoxycholic acid with 1 fewer methylene group in its side chain.


METHODS
Mdr2(-/-) mice were fed a diet containing 24-norUrsodeoxycholic acid (0.5% wt/wt) or ursodeoxycholic acid (0.5% wt/wt) as a clinical comparator for 4 weeks; controls received standard chow. Effects on serum liver tests, liver histology, markers of inflammation and fibrosis, and bile acid transport and metabolism were compared. 24-norUrsodeoxycholic acid metabolism was studied in serum, liver, bile, and urine.


RESULTS
24-norUrsodeoxycholic acid markedly improved liver tests and liver histology and significantly reduced hydroxyproline content and the number of infiltrating neutrophils and proliferating hepatocytes and cholangiocytes. 24-norUrsodeoxycholic acid underwent extensive phase I/II metabolism (hydroxylation, sulfation, and glucuronidation), thereby increasing the hydrophilicity of biliary bile acid secretion. There was a coordinated induction of bile acid detoxifying enzymes (Cyp2b10, Cyp3a11, and Sult2a1) and efflux pumps (Mrp3 and Mrp4). Ursodeoxycholic acid, in contrast, increased alanine transaminase and alkaline phosphatase levels, had no significant effects on hydroxyproline content, and induced biliary transporters and detoxification enzymes to a much smaller extent than 24-norUrsodeoxycholic acid.


CONCLUSIONS
24-norUrsodeoxycholic acid ameliorates sclerosing cholangitis in Mdr2(-/-) mice. Its therapeutic mechanisms involve (1) increasing the hydrophilicity of biliary bile acids, (2) stimulating bile flow with flushing of injured bile ducts, and (3) inducing detoxification and elimination routes for bile acids.
Fickert
Peter
P
Department of Medicine, Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University Graz, Austria.
Wagner
Martin
M
Marschall
Hanns-Ulrich
HU
Fuchsbichler
Andrea
A
Zollner
Gernot
G
Tsybrovskyy
Oleksiy
O
Zatloukal
Kurt
K
Liu
Jie
J
Waalkes
Michael P
MP
Cover
Cathleen
C
Denk
Helmut
H
Hofmann
Alan F
AF
Jaeschke
Hartmut
H
Trauner
Michael
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D015209:Cholangitis, Sclerosing / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D014580:Ursodeoxycholic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C081331:24-norursodeoxycholic acid