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Journal of Cell Science, Vol 107, Issue 12 3281-3290, Copyright © 1994 by Company of Biologists

JOURNAL ARTICLES

Drug efflux mediated by the human multidrug resistance P-glycoprotein is inhibited by cell swelling

A Sardini, GM Mintenig, MA Valverde, FV Sepulveda, DR Gill, SC Hyde, CF Higgins and PA McNaughton
Department of Physiology, King's College London, UK.

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.


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H. R. Goodfellow, A. Sardini, S. Ruetz, R. Callaghan, P. Gros, P. A. McNaughton, and C. F. Higgins
Protein Kinase C-mediated Phosphorylation Does Not Regulate Drug Transport by the Human Multidrug Resistance P-glycoprotein
J. Biol. Chem., June 7, 1996; 271(23): 13668 - 13674.
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© The Company of Biologists Ltd 1994