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Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

Zainab M Mahdi1, Uta Synal-Hermanns1, Aylin Yoker1

  • 1Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.M.M., U.S.-H., A.Y., B.S.); and Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland (K.P.L.).

Molecular Pharmacology
|April 27, 2016
PubMed

Insights

Certain antifungal azoles inhibit multidrug resistance protein 3 (MDR3), impacting phospholipid secretion and potentially worsening drug-induced liver injury. This study establishes a new model to screen for MDR3 and bile salt export pump (BSEP) inhibitors.

Area of Science:

  • Hepatology and Pharmacology
  • Cell Biology and Drug Transport

Background:

  • Drug-induced liver injury is a significant cause of hospitalization.
  • While bile salt export pump (BSEP) inhibition is studied, the role of multidrug resistance protein 3 (MDR3) in drug-induced cholestasis is poorly understood.

Purpose of the Study:

  • To investigate drug interactions with MDR3 and their effects on canalicular lipid secretion.
  • To establish a novel in vitro model for studying MDR3 function.

Main Methods:

  • LLC-PK1 cells were transfected with human transporters (MDR3, BSEP, etc.) and cultured in a Transwell system.
  • Assessed apical phospholipid secretion and taurocholate transport.
  • Evaluated the impact of selected drugs on MDR3-mediated phospholipid secretion and BSEP inhibition.

Main Results:

  • The cell line model demonstrated vectorial bile salt transport and phosphatidylcholine secretion.
  • Antifungal azoles (posaconazole, itraconazole, ketoconazole) significantly inhibited MDR3-mediated phosphatidylcholine secretion.
  • Amoxicillin clavulanate and troglitazone did not affect MDR3 activity; MDR3 inhibitors did not inhibit BSEP.

Conclusions:

  • The developed cell line system effectively models MDR3-mediated phospholipid secretion and allows for parallel screening of MDR3 and BSEP inhibitors.
  • The cholestatic potential of drugs may be exacerbated by the combined inhibition of BSEP and MDR3.

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