Differential transport properties of two mdr gene products are distinguished by progesterone.
P-glycoprotein is an integral membrane protein that is overproduced in multidrug-resistant cells. It is likely to function as an energy-dependent drug efflux pump to maintain intracellular drug concentrations below cytotoxic levels. Individually isolated multidrug-resistant murine cell lines, J7.V1-1 and J7.V3-1, overproduce P-glycoproteins encoded by the mdr1b and mdr1a genes, respectively. The transport properties of these cell lines and the drug binding characteristics of their P-glycoproteins have been compared. It is concluded that 1) the mdr1a gene product is a more efficient efflux pump than the mdr1b gene product, and 2) whereas a single class of vinblastine binding sites is present in J7.V1-1 membrane vesicles, there appears to be two classes of such sites in J7.V3-1 membrane vesicles. The effects of verapamil and progesterone, two compounds that are known to interact with P-glycoprotein, have been analyzed in the two cell lines. Progesterone inhibited drug binding and efflux and increased drug sensitivity to vinblastine with more potency in J7.V1-1 cells than in J7.V3-1 cells. It is concluded that progesterone, but not verapamil, can be used to differentiate the two mdr gene products in the mouse.
Yang
C P
CP
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
Cohen
D
D
Greenberger
L M
LM
Hsu
S I
SI
Horwitz
S B
SB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D011374:Progesterone / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011374:Progesterone; D014747:Vinblastine; D014700:Verapamil