Int J Biochem Mol Biol 2011;2(3):219-227

Original Article
Altered intracellular pH regulation in cells with high levels of P-glycoprotein expression

Gregory Young, Luis Reuss, Guillermo A. Altenberg

Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences
Center, Lubbock, Texas, USA

Received April 27, 2011; accepted May 4, 2011; Epub June 3, 2010; Published August 30, 2011

Abstract: P-glycoprotein is an ATP-binding-cassette transporter that pumps many structurally unrelated drugs out of cells through an
ATP-dependent mechanism. As a result, multidrug-resistant cells that overexpress P-glycoprotein have reduced intracellular steady-state
levels of a variety of chemotherapeutic agents. In addition, increased cytosolic pH has been a frequent finding in multidrug-resistant cells that
express P-glycoprotein, and it has been proposed that this consequence of P-glycoprotein expression may contribute to the lower intracellular
levels of chemotherapeutic agents. In these studies, we measured intracellular pH and the rate of acid extrusion in response to an acid load in
two cells with very different levels of P-glycoprotein expression: V79 parental cells and LZ-8 multidrug resistant cells. Compared to the wild-type
V79 cells, LZ-8 cells have a lower intracellular pH and a slower recovery of intracellular pH after an acid load. The data also show that LZ-8
cells have reduced ability to extrude acid, probably due to a decrease in Na+/H+ exchanger activity. The alterations in intracellular pH and acid
extrusion in LZ-8 cells are reversed by 24-h exposure to the multidrug-resistance modulator verapamil. The lower intracellular pH in LZ-8
indicates that intracellular alkalinization is not necessary for multidrug resistance. The reversal by verapamil of the decreased acid-extrusion
suggests that P-glycoprotein can affect other membrane transport mechanism. (IJBMB1104008).

Keywords: MDR1, Na+/H+ exchanger, verapamil, multidrug resistance, Adriamycin, intracellular pH regulation

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Address all correspondence to:
Guillermo Altenberg, M.D., Ph.D.
Department of Cell Physiology and Molecular Biophysics
Texas Tech University Health Sciences Center
Lubbock, Texas 79430-6551
Tel: (806) 743-2531
Fax: (806) 743-1512