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J. Biol. Chem., Vol. 265, Issue 18, 10282-10288, 06, 1990

Differential transport properties of two mdr gene products are distinguished by progesterone

CP Yang, D Cohen, LM Greenberger, SI Hsu and SB Horwitz
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.

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.
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