Effect of P-glycoprotein modulators on the human extraneuronal monoamine transporter

The aim of this work was to investigate the effect of P-glycoprotein modulators on human extraneuronal monoamine transporter (EMT)-mediated transport. The experiments were performed using a cell line From human embryonic kidney (HEK293 cells) stably transfected with pcDNA3hEMT (293(hEMT)), or with pcDNA3 alone (293(control)). Of the P-glycoprotein modulators tested, rhodamine123. verapamil and daunomycin concentration-dependently inhibited EMT-mediated uptake of [H-3]1-methyl-4-phenylpyridinium ([H-3]MPP+). The corresponding IC50's were found to be 3.6, 37 and 130 muM, respectively. By contrast, vinblastine, digitoxin and cyclosporine A were devoid of effect. The endogenous organic cation tyramine, but not choline, inhibited EMT-mediated transport (IC50 of 468 muM). Moreover, L-arginine and L-histidine (up to 1 mM) did not affect [H-3]MPP+ uptake. Finally, MPP+ and tyramine trans-stimulated [H-3]MPP+ uptake, but rhodamine 123 had no effect, and verapamil and daunomycin trans-inhibited [H-3]MPP+ uptake. In conclusion, this study shows that several cationic modulators of P-glycoprotein inhibit EMT-mediated transport. As a consequence, the interaction of P-glycoprotein modulators with EMT must be taken into account, and the consequences of this interaction must not be forgotten when using such drugs in vivo. (C) 2001 Elsevier Science B.V. All rights reserved.