Mdr1/p-glycoprotein function: ii - effect of hypotonicity and
inhibitors on chloride efflux and volume regulation.
Weaver, James L., Adorjan Aszalos, and Leslie McKinney.
Molecular Pharmacology, DRT, CDER, FDA, Laurel, MD; Department of
Physiology, AFRRI, Bethesda, MD
APStracts 2:0388C, 1995.
Resistance to anti-tumor drugs can be mediated by overexpression of
the MDR1 protein (P-glycoprotein). In three MDR1-transfected cell
lines, (Gill et al. Cell 71:23-32, 1992; Altenberg, et al. Cancer
Research 54:618-622, 1994), a hypotonic stress-induced Cl- current
has been demonstrated that can be inhibited by MDR1 substrates and
Cl- channel blockers. We tested the hypothesis that MDR1 expression
confers additional Cl- conductance by measuring regulatory volume
decrease (RVD) in four pairs of isogenic cell lines, and 36Cl-efflux
in two cell lines with and without hypotonic stress. The kinetics of
RVD and response to Cl- channel blockers were indistinguishable in
MDR and parental cells. Additionally, no significant difference was
seen between 36Cl-efflux rate constants under hypotonic conditions
between NIH3T3 and L1210 parental and MDR cells. We conclude that, in
intact cells, the expression of MDR1 does not alter the rate of
volume regulation or the rate of 36Cl-efflux under hypotonic
conditions between parental and MDR cells.
Received 10 August 1995; accepted in final form 23 October 1995.
APS Manuscript Number C500-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95