CHANGES IN INTRACELLULAR OR EXTRACELLULAR PH DO NOT MEDIATE P-GLYCOPROTEIN-DEPENDENT MULTIDRUG-RESISTANCE

P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) is thought to result from active extrusion of lipid-soluble, titratable chemotherap eutic agents. Given the lack of demonstration of coupling between ATP hydrolysis and drug transport, the resistance to chemically unrelated compounds, and findings of elevated intracellular pH (pH(i)), it has b een proposed that reduced intracellular accumulation of drugs in MDR i s due to changes in the pH difference across the plasma membrane. Elev ation of pH(i) or decrease in local extracellular pH (pH(o)) could red uce the intracellular accumulation of the protonated chemotherapeutic drugs and account for Pgp-mediated MDR. Alternatively, changes in pH(i ) or pH(o) could increase drug efflux by other mechanisms, such as cou pled transport involving H+ or OH-, or allosteric effects on Pgp or ot her proteins. Both mechanisms could operate independently of the charg e of the substrate. The possibility of a role of pH(i) in drug efflux is important to test because of the clinical significance of the pheno menon of MDR of tumors. We tested this hypothesis and found that MDR c an occur in cells with low, normal, or high pH(i). Further, resistant cells exhibited reduced steady-state drug accumulation and increased e fflux without changes in local pH(o). Finally, acute changes in pH(i) had no appreciable effect on Pgp-mediated drug efflux. We conclude tha t Pgp-mediated MDR is not a consequence of changes in pH(i) or pH(o).