title: Effect of P-glycoprotein modulators on the human extraneuronal monoamine transporter.
abstract: 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 [3H]1-methyl-4-phenylpyridinium ([3H]MPP(+)). The corresponding IC(50)'s were found to be 3.6, 37 and 130 microM, respectively. By contrast, vinblastine, digitoxin and cyclosporine A were devoid of effect. The endogenous organic cation tyramine, but not choline, inhibited EMT-mediated transport (IC(50) of 468 microM). Moreover, L-arginine and L-histidine (up to 1 mM) did not affect [3H]MPP(+) uptake. Finally, MPP(+) and tyramine trans-stimulated [3H]MPP(+) uptake, but rhodamine123 had no effect, and verapamil and daunomycin trans-inhibited [3H]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.
authors: Department of Biochemistry, Faculty of Medicine, 4200-319 Porto, Portugal. fmartel@med.up.pt
authors: F
authors: F
authors: Martel
authors: E
authors: E
authors: Keating
authors: I
authors: I
authors: Azevedo
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D001120:Arginine / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002412:Cations / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006639:Histidine / Q000494:pharmacology; D006801:Humans; D027701:Organic Cation Transport Proteins; D020112:Rhodamine 123 / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium; D014439:Tyramine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology; D000099254:Organic Cation Transporter 3
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001120:Arginine; D002352:Carrier Proteins; D002412:Cations; D016572:Cyclosporine; D003630:Daunorubicin; D006639:Histidine; D027701:Organic Cation Transport Proteins; D020112:Rhodamine 123; D014316:Tritium; D014439:Tyramine; D014700:Verapamil; D014747:Vinblastine; D000099254:Organic Cation Transporter 3