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24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.

Abstract：

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 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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Fickert P,Wagner M,Marschall HU,Fuchsbichler A,Zollner G,Tsybrovskyy O,Zatloukal K,Liu J,Waalkes MP,Cover C,Denk H,Hofmann AF,Jaeschke H,Trauner M

doi

10.1053/j.gastro.2005.10.018

keywords:

subject

Has Abstract

pub_date

2006-02-01 00:00:00

pages

465-81

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(05)02174-8

journal_volume

130

pub_type

杂志文章

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24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.