| Conjugation is essential for the anticholestatic effect of NorUrsodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver. | |
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MedLine Citation:
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PMID: 21038414 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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NorUDCA (24-norursodeoxycholic acid), the C₂₃-homolog of ursodeoxycholic acid (UDCA), showed remarkable therapeutic effects in cholestatic Mdr2 (Abcb4) (multidrug resistance protein 2/ATP-binding cassette b4) knockout mice with sclerosing/fibrosing cholangitis. In contrast to UDCA, norUDCA is inefficiently conjugated in human and rodent liver, and conjugation has been discussed as a key step for the anticholestatic action of UDCA in cholestasis. We compared the choleretic, anticholestatic, and antiapoptotic properties of unconjugated and taurine-conjugated UDCA (C₂₄) and norUDCA (C₂₃) in isolated perfused rat liver (IPRL) and in natrium/taurocholate cotransporting polypeptide (Ntcp)-transfected human hepatoma (HepG2) cells. Taurolithocholic acid (TLCA) was used to induce a predominantly hepatocellular cholestasis in IPRL. Bile flow was determined gravimetrically; bile acids determined by gas chromatography and liquid chromatography/tandem mass spectrometry; the Mrp2 model substrate, 2,4-dinitrophenyl-S-glutathione (GS-DNP) was determined spectrophotometrically; and apoptosis was determined immunocytochemically. The choleretic effect of C₂₃-bile acids was comparable to their C₂₄-homologs in IPRL. In contrast, TnorUDCA, but not norUDCA antagonized the cholestatic effect of TLCA. Bile flow (percent of controls) was 8% with TLCA-induced cholestasis, and unchanged by coinfusion of norUDCA (14%). However, it was increased by TnorUDCA (83%), UDCA (73%) and TUDCA (136%). Secretion of GS-DNP was markedly reduced by TLCA (5%), unimproved by norUDCA (4%) or UDCA (17%), but was improved modestly by TnorUDCA (26%) or TUDCA (58%). No apoptosis was observed in IPRL exposed to low micromolar TLCA, but equivalent antiapoptotic effects of TUDCA and TnorUDCA were observed in Ntcp-HepG2 cells exposed to TLCA. CONCLUSION: Conjugation is essential for the anticholestatic effect of norUDCA in a model of hepatocellular cholestasis. Combined therapy with UDCA and norUDCA may be superior to UDCA or norUDCA monotherapy in biliary disorders in which hepatocyte as well as cholangiocyte dysfunction contribute to disease progression. |
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Authors:
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Gerald U Denk; Silvia Maitz; Ralf Wimmer; Christian Rust; Pietro Invernizzi; Sacha Ferdinandusse; Wim Kulik; Andrea Fuchsbichler; Peter Fickert; Michael Trauner; Alan F Hofmann; Ulrich Beuers |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 52 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-01 Completed Date: 2010-11-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1758-68 Citation Subset: IM |
Affiliation:
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Department of Medicine II, Klinikum Großhadern, University of Munich, Munich, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Bile / secretion Bile Acids and Salts / metabolism Carcinoma, Hepatocellular / pathology Cholangitis / drug therapy Cholestasis / chemically induced* Chromatography, Gas Hepatoblastoma / pathology Humans Liver / drug effects, metabolism Liver Diseases / etiology* Liver Neoplasms / pathology Male Mice Rats Rats, Sprague-Dawley Taurine / metabolism Taurolithocholic Acid / adverse effects* Ursodeoxycholic Acid / therapeutic use |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 107-35-7/Taurine; 128-13-2/Ursodeoxycholic Acid; 516-90-5/Taurolithocholic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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