MDR1/P-glycoprotein function. II. Effect of hypotonicity and inhibitors on Cl- efflux and volume regulation.

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.