24-norUrsodeoxycholic Acid - Superior to Ursodeoxycholic Acid in PSC

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Gastroenterology. 2006 Feb;130(2):465-81.

24-norUrsodeoxycholic

Acid Is Superior to Ursodeoxycholic

Acid in the Treatment of Sclerosing Cholangitis in Mdr2 (Abcb4) Knockout Mice.

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.

Depart Medicine, Laboratory of Experimental & Molecular Hepatology, Medical

University, Graz, Austria.

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.

PMID: 16472600 [PubMed - in process]

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