title: Specific inhibitors distinguish the chloride channel and drug transporter functions associated with the human multidrug resistance P-glycoprotein.
abstract: Expression of the human multidrug resistance P-glycoprotein is associated with two activities, active drug transport and a volume-regulated chloride channel. In this study we define four classes of compound, based on their differential effects on these two activities. Class I compounds are substrates transported by P-glycoprotein. They also prevent channel activation when added to the cytoplasmic face of the membrane. Class II compounds include reversers of multidrug resistance such as verapamil. These compounds inhibit drug transport and block the chloride channel when added to the outer face of the membrane. Class III compounds include conventional channel blockers which block the chloride channel but do not influence drug transport. Class IV compounds, for example cyclosporin A, appear to inhibit drug transport but do not affect chloride channel activity. These findings have implications for the relationship between the channel and transporter functions associated with P-glycoprotein expression, and for the development of clinical agents which reverse multidrug resistance.
authors.affiliation: AFRC Institute of Animal Physiology and Genetics Research, Babraham, Cambridge, UK.
authors.forename: G M
authors.initials: GM
authors.lastname: Mintenig
authors.forename: M A
authors.initials: MA
authors.lastname: Valverde
authors.forename: F V
authors.initials: FV
authors.lastname: Sepulveda
authors.forename: D R
authors.initials: DR
authors.lastname: Gill
authors.forename: S C
authors.initials: SC
authors.lastname: Hyde
authors.forename: J
authors.initials: J
authors.lastname: Kirk
authors.forename: C F
authors.initials: CF
authors.lastname: Higgins
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003524:Cyclosporins / Q000493:pharmacokinetics / Q000494:pharmacology; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D004594:Electrophysiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009579:Nitrobenzoates / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection; D014700:Verapamil / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D018118:Chloride Channels; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D009579:Nitrobenzoates; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D014700:Verapamil; D003630:Daunorubicin