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Multidrug resistance protein 1-mediated transport of saquinavir by microglia

Shannon Dallas1, Patrick T Ronaldson, Moise Bendayan

  • 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario M5S 2S2, Canada.

Neuroreport
|May 7, 2004
PubMed

Insights

Multidrug resistance protein-1 (MRP1) in microglia contributes to low brain penetration of the HIV protease inhibitor saquinavir. This transporter is located on the cell surface, mediating drug export.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • The human immunodeficiency virus (HIV) protease inhibitor saquinavir's distribution in the central nervous system (CNS) may be regulated by efflux transporters.
  • Multidrug resistance-associated protein 1 (MRP1) is an ATP-dependent efflux transporter expressed in brain cells, including microglia, a key target for HIV.

Purpose of the Study:

  • To investigate the subcellular localization of MRP1 in a microglia cell line.
  • To demonstrate MRP1-mediated export of saquinavir from microglia.

Main Methods:

  • Immunogold cytochemistry was used to determine MRP1 subcellular localization in the MLS-9 microglia cell line.
  • Radiolabeled saquinavir ([14C]saquinavir) efflux assays were performed in MLS-9 cell monolayers.
  • The effect of known MRP1 inhibitors on saquinavir efflux was evaluated.

Main Results:

  • MRP1 was primarily localized to the plasma membrane of MLS-9 microglia cells.
  • Efflux of [14C]saquinavir from MLS-9 cell monolayers was observed.
  • Established MRP1 inhibitors significantly reduced saquinavir efflux, confirming MRP1's role.

Conclusions:

  • MRP1 is present on the plasma membrane of microglia and actively exports saquinavir.
  • MRP1 contributes to the limited penetration of protease inhibitors into the brain.
  • Targeting MRP1 could potentially enhance CNS delivery of HIV protease inhibitors.

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