Mdr1/p-glycoprotein function: i - effect of hypotonicity and
inhibitors on rhodamine 123 exclusion.
Weaver, James L., Leslie McKinney, Patricia V. Schoenlein, Sarah
Goldenberg, Michael M. Gottesman, and Adorjan Aszalos.
Molecular Pharmacology, DRT, CDER, FDA, Laurel, MD; Department of
Physiology, AFRRI, Bethesda, MD; Department of Anatomy & Cell
Biology, Medical College of Georgia, Augusta, GA, Laboratory of Cell
Biology, NCI, NIH, Bethesda, MD
APStracts 2:0387C, 1995.
The MDR1 protein (P-glycoprotein) is a membrane ATPase whose
expression results in resistance to several anti-tumor drugs. It has
been proposed that the MDR1 protein, in addition to its pump-like
properties, can function as (Gill et al., Cell 71:23-32, 1992,
Altenberg et al., Cancer Research 54:618-622, 1994), or mediate the
activity of (Hardy et al., EMBO J 14:68-75, 1995) a hypotonic stress
-induced Cl- current. In addition, one study found that drug transport
and Cl- channel-associated functions of MDR1 were separable and
mutually exclusive, and that when cells are swelled, the MDR1 protein
cannot transport substrate. This hypothesis was tested in four pairs
of isogenic cell lines with MDR1 transfectants expressing 8,000 to
55,000 MDR1 antibody binding sites/cell. Cytoplasmic exclusion of
rhodamine 123 was used as an indicator of MDR1 function to measure
the effect of hypotonic stress, MDR1 inhibitors, and Cl- channel
blockers on MDR1 transport function. It was found that MDR1 activity
and its inhibition by cyclosporine A or flufenamic acid were
unaffected by hypotonicity alone or in combination with Cl- channel
blockers.
Received 10 August 1995; accepted in final form 23 October 1995.
APS Manuscript Number C499-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95