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MDR1/P-glycoprotein function. II. Effect of hypotonicity and inhibitors on Cl- efflux and volume regulation
J L Weaver1, A Aszalos, L McKinney
1Division of Research and Testing, Food and Drug Administration, Laurel, Maryland 20708, USA.
Abstract:
Resistance to anti-tumor drugs can be mediated by overexpression of the multidrug resistance 1 (MDR1) protein (P-glycoprotein). In three MDR1-transfected cell lines (Gill et al. Cell 71: 23-32, 1992; Altenberg et al. Cancer Res. 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 NIH/3T3 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 36Cl efflux under hypotonic conditions between parental and MDR cells.
Insights
Multidrug resistance 1 (MDR1) protein overexpression does not affect cell volume regulation or chloride efflux under hypotonic stress. This study found no difference in these processes between MDR1-expressing and parental cells.
Area of Science:
- Cellular Physiology
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance 1 (MDR1) protein, also known as P-glycoprotein, is implicated in anti-tumor drug resistance.
- Previous studies suggested MDR1-transfected cells exhibit hypotonic stress-induced chloride currents inhibited by MDR1 substrates.
Purpose of the Study:
- To investigate whether MDR1 expression confers additional chloride conductance in intact cells.
- To determine the impact of MDR1 on regulatory volume decrease (RVD) and chloride efflux under hypotonic conditions.
Main Methods:
- Measurement of regulatory volume decrease (RVD) in four pairs of isogenic cell lines.
- Assessment of 36Cl efflux in two cell lines under hypotonic stress.
- Evaluation of responses to chloride channel blockers.
Main Results:
- RVD kinetics and response to chloride channel blockers were identical in MDR1-expressing and parental cells.
- No significant difference in 36Cl efflux rate constants under hypotonic conditions was observed between parental and MDR1-expressing cells.
- MDR1 expression did not alter the rate of volume regulation or chloride efflux.
Conclusions:
- In intact cells, MDR1 expression does not confer additional chloride conductance.
- The rate of volume regulation and 36Cl efflux under hypotonic conditions are not affected by MDR1 expression.