Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

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

Takashi Yoshikado, Tappei Takada, Takehito Yamamoto, Hiroko Yamaji, Kousei Ito, Tomofumi Santa, Hiromitsu Yokota, Yutaka Yatomi, Haruhiko Yoshida, Jun Goto, Shoji Tsuji and Hiroshi Suzuki
Molecular Pharmacology February 2011, 79 (2) 241-250; DOI: https://doi.org/10.1124/mol.110.067256
Takashi Yoshikado
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tappei Takada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takehito Yamamoto
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroko Yamaji
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kousei Ito
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomofumi Santa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiromitsu Yokota
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yutaka Yatomi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haruhiko Yoshida
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jun Goto
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shoji Tsuji
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroshi Suzuki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

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 [14C]phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [3H]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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Research on Human Genome Tailor Made from the Ministry of Health, Labor, and Welfare of Japan [Grant H19-Genome-Ippan-004].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.067256.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    ALP
    alkaline phosphatase
    ALT
    alanine aminotransferase
    AST
    aspartate aminotransferase
    BSEP
    bile salt export pump
    DILI
    drug-induced liver injury
    EGFP
    enhanced green fluorescent protein
    γ-GTP
    γ-glutamyl transpeptidase
    ITZ
    itraconazole
    LFT
    liver function test
    LLC-BSEP/NTCP
    bile salt export pump- and Na+/taurocholate cotransporting polypeptide-expressing LLC-PK1 cell
    LLC-EGFP
    enhanced green fluorescent protein-expressing LLC-PK1 cell
    LLC-EGFP/NTCP
    enhanced green fluorescent protein- and Na+/taurocholate cotransporting polypeptide-expressing LLC-PK1 cell
    LLC-MDR3
    multidrug resistance 3 P-glycoprotein-expressing LLC-PK1 cell
    MDR3
    multidrug resistance 3 P-glycoprotein
    MOI
    multiplicity of infection
    NTCP
    Na+/taurocholate cotransporting polypeptide
    PC
    phosphatidylcholine
    PFIC
    progressive familial intrahepatic cholestasis
    PS
    permeability-surface area product
    ANOVA
    analysis of variance
    HP-β-CD
    hydroxypropyl-β-cyclodextrin
    UPLC-MS/MS
    ultraperformance liquid chromatography/tandem mass spectrometry.

  • Received July 1, 2010.
  • Accepted November 4, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

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

Takashi Yoshikado, Tappei Takada, Takehito Yamamoto, Hiroko Yamaji, Kousei Ito, Tomofumi Santa, Hiromitsu Yokota, Yutaka Yatomi, Haruhiko Yoshida, Jun Goto, Shoji Tsuji and Hiroshi Suzuki
Molecular Pharmacology February 1, 2011, 79 (2) 241-250; DOI: https://doi.org/10.1124/mol.110.067256

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

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

Takashi Yoshikado, Tappei Takada, Takehito Yamamoto, Hiroko Yamaji, Kousei Ito, Tomofumi Santa, Hiromitsu Yokota, Yutaka Yatomi, Haruhiko Yoshida, Jun Goto, Shoji Tsuji and Hiroshi Suzuki
Molecular Pharmacology February 1, 2011, 79 (2) 241-250; DOI: https://doi.org/10.1124/mol.110.067256
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Action of Org 34167 on HCN channels
  • The effects of echinocystic acid on Kv7 channels
  • Cysteine151 in Keap1 Drives CDDO-Me Pharmacodynamic Action
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics