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P-glycoprotein (P-gp), the product of the human multidrug resistance (MDR1) gene, confers multidrug resistance on cells by acting as an ATP-dependent drug transporter. A method using confocal microscopy was developed to measure the transport activity of P-gp from the rate of movement of doxorubicin, a fluorescent substrate of P-gp, across the membrane of a single cell. Recent work has shown that expression of P-gp enhances the activation of chloride channels in response to cell swelling, suggesting that membrane stretch might switch P-gp from a drug-transporting mode to a mode in which it activates chloride channels. In agreement with this idea, we find that cell swelling inhibits drug efflux in cells expressing P-gp but is without effect on the slower background efflux in cells not expressing P-gp and in cells transiently transfected with a mutated MDR1 in which the ATP hydrolysis sites had been inactivated. The identification of a novel means for inhibiting P-gp-mediated drug transport may have implications for the reversal of multidrug resistance during chemotherapy.

Type

Journal article

Journal

J Cell Sci

Publication Date

12/1994

Volume

107 ( Pt 12)

Pages

3281 - 3290

Keywords

3T3 Cells, ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Biological Transport, Cell Compartmentation, Cell Membrane Permeability, Chloride Channels, Colforsin, Doxorubicin, Drug Resistance, Multiple, Humans, Mice, Microscopy, Confocal, Osmotic Pressure, Recombinant Proteins, Verapamil