MDR1 P-GLYCOPROTEIN FUNCTION .2. EFFECT OF HYPOTONICITY AND INHIBITORS ON CL- EFFLUX AND VOLUME REGULATION/

Resistance to anti-tumor drugs can be mediated by overexpression of th e multidrug resistance 1 (MDR1) protein (P-glycoprotein). In three MDR 1-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 expressi on confers additional Cl- conductance by measuring regulatory volume d ecrease (RVD) in four pairs of isogenic cell lines and Cl-36 efflux in two cell lines with and without hypotonic stress. The kinetics of RVD and response to Cl- channel blockers were indistinguishable in MDR an d parental cells. Additionally, no significant difference was seen bet ween Cl-36 efflux rate constants under hypotonic conditions between NI H/3T3 and L1210 parental and MDR cells. We conclude that, in intact ce lls, the expression of MDR1 does not alter the rate of volume regulati on or the rate of Cl-36 efflux under hypotonic conditions between pare ntal and MDR cells.