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24-norUrsodeoxycholic Acid Is Superior to Ursodeoxycholic Acid in the Treatment of Sclerosing Cholangitis in Mdr2 (Abcb4) Knockout Mice

2006; Elsevier BV; Volume: 130; Issue: 2 Linguagem: Inglês

10.1053/j.gastro.2005.10.018

1528-0012

Peter Fickert, Martin Wagner, Hanns‐Ulrich Marschall, Andrea Fuchsbichler, Gernot Zollner, Oleksiy Tsybrovskyy, Kurt Zatloukal, Jie Liu, Michael P. Waalkes, Cathleen Cover, Helmut Denk, Alan F. Hofmann, Hartmut Jaeschke, Michael Trauner,

Liver Disease Diagnosis and Treatment

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- nor Ursodeoxycholic 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- nor Ursodeoxycholic 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- nor Ursodeoxycholic acid metabolism was studied in serum, liver, bile, and urine. Results: 24- nor Ursodeoxycholic 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- nor Ursodeoxycholic 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- nor Ursodeoxycholic acid. Conclusions: 24- nor Ursodeoxycholic 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.