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.
Drug efflux mediated by the human multidrug resistance P-glycoprotein is inhibited by cell swelling
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A. Sardini, G.M. Mintenig, M.A. Valverde, F.V. Sepulveda, D.R. Gill, S.C. Hyde, C.F. Higgins, P.A. McNaughton; Drug efflux mediated by the human multidrug resistance P-glycoprotein is inhibited by cell swelling. J Cell Sci 1 December 1994; 107 (12): 3281–3290. doi: https://doi.org/10.1242/jcs.107.12.3281
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