| Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4. | |
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MedLine Citation:
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PMID: 21056966 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Biliary secretion of bile acids and phospholipids, both of which are essential components of biliary micelles, are mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance 3 P-glycoprotein (MDR3/ABCB4), respectively, and their genetic dysfunction leads to the acquisition of severe cholestatic diseases. In the present study, we found two patients with itraconazole (ITZ)-induced cholestatic liver injury with markedly high serum ITZ concentrations. To characterize the effect of ITZ on bile formation in vivo, biliary bile acids and phospholipids were analyzed in ITZ-treated rats, and it was revealed that biliary phospholipids, rather than bile acids, were drastically reduced in the presence of clinically relevant concentrations of ITZ. Moreover, by using MDR3-expressing LLC-PK1 cells, we found that MDR3-mediated efflux of [(14)C]phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [(3)H]taurocholate was not significantly affected by ITZ, which is consistent with our in vivo observations. In conclusion, this study suggests the involvement of the inhibition of MDR3-mediated biliary phospholipids secretion in ITZ-induced cholestasis. Our approach may be useful for analyzing mechanisms of drug-induced cholestasis and evaluating the cholestatic potential of clinically used drugs and drug candidates. |
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Authors:
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Takashi Yoshikado; Tappei Takada; Takehito Yamamoto; Hiroko Yamaji; Kousei Ito; Tomofumi Santa; Hiromitsu Yokota; Yutaka Yatomi; Haruhiko Yoshida; Jun Goto; Shoji Tsuji; Hiroshi Suzuki |
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Publication Detail:
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Type: Journal Article Date: 2010-11-05 |
Journal Detail:
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Title: Molecular pharmacology Volume: 79 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 241-50 Citation Subset: IM |
Affiliation:
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Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. tappei-tky@umin.ac.jp. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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