論文

査読有り
2011年2月

Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4

MOLECULAR PHARMACOLOGY
  • Takashi Yoshikado
  • ,
  • Tappei Takada
  • ,
  • Takehito Yamamoto
  • ,
  • Hiroko Yamaji
  • ,
  • Kousei Ito
  • ,
  • Tomofumi Santa
  • ,
  • Hiromitsu Yokota
  • ,
  • Yutaka Yatomi
  • ,
  • Haruhiko Yoshida
  • ,
  • Jun Goto
  • ,
  • Shoji Tsuji
  • ,
  • Hiroshi Suzuki

79
2
開始ページ
241
終了ページ
250
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1124/mol.110.067256
出版者・発行元
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

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.

Web of Science ® 被引用回数 : 52

リンク情報
DOI
https://doi.org/10.1124/mol.110.067256
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000286311800004&DestApp=WOS_CPL

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