Multidrug resistance protein 1-mediated transport of saquinavir by microglia.
Regulation of CNS distribution of the human immunodeficiency virus (HIV) protease inhibitor saquinavir may involve ATP-dependent membrane-bound efflux transport proteins that are expressed in several brain cellular compartments. We recently characterized molecular and functional expression of one such transporter, multidrug resistance protein-1 (MRP1) in microglia, the primary brain cellular target of HIV. In the present study, we further examine subcellular localization of MRP1 in a microglia cell line (MLS-9) using immunogold cytochemistry and directly demonstrate MRP1-mediated export of saquinavir. MRP1 localized primarily to the plasma membrane of the MLS-9 cells. [14C]Saquinavir efflux by MLS-9 monolayers was inhibited by well-established MRP1 inhibitors. These results indicate that MRP1 contributes, in part, to the overall low permeation of protease inhibitors in the brain.
Dallas
Shannon
S
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario M5S 2S2, Canada.
Ronaldson
Patrick T
PT
Bendayan
Moise
M
Bendayan
Reina
R
D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D002460:Cell Line; D017628:Microglia / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D051381:Rats; D019258:Saquinavir / Q000378:metabolism*
D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019258:Saquinavir; C421109:multidrug resistance-associated protein 1