NDLI: Changes in intra- or extracellular pH do not mediate P-glycoprotein-dependent multidrug resistance.

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Changes in intra- or extracellular pH do not mediate P-glycoprotein-dependent multidrug resistance.

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Changes in intra- or extracellular pH do not mediate P-glycoprotein-dependent multidrug resistance.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Young, G. Horton, J. K. Reuss, L. Altenberg, G. A. Belli, J. A. Glass, D.
Description	Author Affiliation: Altenberg GA ( Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston 77555-0641.);
Abstract	P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) is thought to result from active extrusion of lipid-soluble, titratable chemotherapeutic agents. Given the lack of demonstration of coupling between ATP hydrolysis and drug transport, the resistance to chemically unrelated compounds, and findings of elevated intracellular pH (pHi), it has been proposed that reduced intracellular accumulation of drugs in MDR is due to changes in the pH difference across the plasma membrane. Elevation of pHi or decrease in local extracellular pH (pHo) could reduce the intracellular accumulation of the protonated chemotherapeutic drugs and account for Pgp-mediated MDR. Alternatively, changes in pHi or pHo could increase drug efflux by other mechanisms, such as coupled transport involving H+ or OH-, or allosteric effects on Pgp or other proteins. Both mechanisms could operate independently of the charge of the substrate. The possibility of a role of pHi in drug efflux is important to test because of the clinical significance of the phenomenon of MDR of tumors. We tested this hypothesis and found that MDR can occur in cells with low, normal, or high pHi. Further, resistant cells exhibited reduced steady-state drug accumulation and increased efflux without changes in local pHo. Finally, acute changes in pHi had no appreciable effect on Pgp-mediated drug efflux. We conclude that Pgp-mediated MDR is not a consequence of changes in pHi or pHo.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	20
Volume Number	90
Language	English
Publisher	National Academy of Sciences
Publisher Date	1993-11-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Carrier Proteins Physiology Membrane Glycoproteins Animals Biological Transport Cell Line Cricetinae Drug Resistance Hydrogen-Ion Concentration In Vitro Techniques P-Glycoprotein Rhodamine 123 Rhodamines Metabolism Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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