TY - JOUR
T1 - 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice
AU - Fickert, Peter
AU - Wagner, Martin
AU - Marschall, Hanns Ulrich
AU - Fuchsbichler, Andrea
AU - Zollner, Gernot
AU - Tsybrovskyy, Oleksiy
AU - Zatloukal, Kurt
AU - Liu, Jie
AU - Waalkes, Michael P.
AU - Cover, Cathleen
AU - Denk, Helmut
AU - Hofmann, Alan F.
AU - Jaeschke, Hartmut
AU - Trauner, Michael
N1 - Funding Information:
Supported by Grants P-15502 and P18613-B05 from the Austrian Science Fund (to M.T.), by the Swedish Research Council and The Swedish Medical Association (H.-U.M.), by National Institutes of Health (NIH) Grant AA12916 (H.J.), by NIH Grant DK 64891 (A.F.H.), and in part by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research.
PY - 2006/2
Y1 - 2006/2
N2 - Background & Aims: 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 C23 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.
AB - Background & Aims: 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 C23 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.
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U2 - 10.1053/j.gastro.2005.10.018
DO - 10.1053/j.gastro.2005.10.018
M3 - Article
C2 - 16472600
AN - SCOPUS:32044467118
SN - 0016-5085
VL - 130
SP - 465
EP - 481
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -