MDR3 P-glycoprotein, a Phosphatidylcholine Translocase, Transports Several Cytotoxic Drugs and Directly Interacts with Drugs as Judged by Interference with Nucleotide Trapping

We report an increased directional transport of several MDR1 P-glycoprotein substrates, such as digoxin, paclitaxel, and vinblastine, through polarized monolayers of MDR3-transfected cells

Alexander J. Smith

2002

Scholarcy highlights

  • The human MDR3 gene is a member of the multidrug resistance gene family
  • Directional transport of the cardiac glycoside digoxin; of the cytostatic drugs paclitaxel, daunorubicin, and vinblastine; and of the antihelmintic drug ivermectin to the apical compartment is significantly increased in the MDR3-transfected cells compared with the parental cell line
  • Previous attempts to demonstrate drug transport by the human MDR3 P-gp and its murine homolog Mdr2 P-gp have met with little success
  • It came as a surprise that expression of MDR3 in kidney cell monolayers results in the directional transport of digoxin, paclitaxel, daunorubicin, vinblastine, and ivermectin
  • The transport of these drugs is specific, since the transport of several other drugs and reversal agents is not increased in the MDR3 transfected cell lines
  • Transport is inhibited by the MDR1 P-gp reversal agents, cyclosporin A, PSC 833, and verapamil, agents that inhibit the translocation of short-chain PC analogs by the MDR3 P-gp
  • More work on the effect of inhibitors on the transport of long-chain PC and on binding of drugs to MDR3 P-gp reconstituted in PC-free membranes is required to fully define the physiological functions of this interesting transporter

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