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Folate concentration dependent transport activity of the Multidrug Resistance Protein 1 (ABCC1)

Jan Hendrik Hooijberg1, Gerrit Jansen, Yehuda G Assaraf

  • 1Department of Pediatric Hematology/Oncology, VU University Medical Center (VUMC), De Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands. jh.hooijberg@vumc.nl

Biochemical Pharmacology
|March 26, 2004
PubMed

Insights

Cellular folate levels impact the drug transport activity of Multidrug Resistance Protein 1 (MRP1/ABCC1). Lowering folate reduces MRP1/ABCC1-mediated daunorubicin efflux, which is restored upon folate repletion.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Multidrug Resistance Protein 1 (MRP1/ABCC1) mediates drug resistance and cellular folate export.
  • The relationship between cellular folate status and MRP1/ABCC1 transport activity is not well understood.

Purpose of the Study:

  • To investigate if cellular folate levels affect the functional activity of MRP1/ABCC1.
  • To determine the impact of folate deprivation and repletion on MRP1/ABCC1-mediated efflux of daunorubicin (DNR).

Main Methods:

  • Utilized human ovarian carcinoma cell lines (2008wt and 2008/MRP1) with varying MRP1/ABCC1 expression.
  • Assessed daunorubicin (DNR) efflux under conditions of folate sufficiency, folate deprivation, and folate repletion.
  • Employed benzbromarone as a specific MRP1 inhibitor.

Main Results:

  • Folate deprivation significantly decreased MRP1/ABCC1-mediated DNR efflux in 2008/MRP1 cells (to 43%) and 2008wt cells (to 84%).
  • Benzbromarone inhibition of DNR efflux was abolished after folate deprivation.
  • Folate repletion fully restored DNR efflux, while MRP1/ABCC1 protein levels and cellular ATP/ADP pools remained unchanged.

Conclusions:

  • Cellular folate status directly influences the transport activity of MRP1/ABCC1.
  • These findings suggest a role for folate homeostasis in modulating ABC transporter function and drug resistance.

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