Inhibition of rhodamine 123 secretion by cyclosporin A as a model of P-glycoprotein mediated transport in liver.
The interaction between P-glycoprotein modulators and P-glycoprotein mediated transport was investigated using rhodamine 123 in the isolated perfused rat liver of a mutant (TR-) rat strain. TR- rats, deficient in the canalicular multispecific anion transport system, are unable to extrude organic anions (glucuronides) and therefore excrete solely unconjugated rhodamine 123 via P-glycoprotein. Cyclosporin A, a modulator of multidrug resistance in tumor cells, inhibited the biliary secretion of rhodamine 123 dose dependently in a non-competitive manner. Both cyclosporin A and rhodamine inhibited photoaffinity labeling of immunoprecipitated P-glycoprotein with azidopine, indicating binding to hepatic P-glycoprotein. Our results indicate that monitoring the biliary rhodamine 123 secretion in the isolated perfused liver of TR- rats offers a new system for testing modulators of P-glycoprotein like cyclosporin A.
Stapf
V
V
Department of General and Experimental Pathology, University of Vienna, AKH.
Thalhammer
T
T
Huber-Huber
R
R
Felberbauer
F
F
Gajdzik
L
L
Graf
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D001386:Azides / Q000378:metabolism; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism; D004351:Drug Resistance; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000964:Antimetabolites, Antineoplastic; D001386:Azides; D002352:Carrier Proteins; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D012235:Rhodamines; D020112:Rhodamine 123; C041130:azidopine; D016572:Cyclosporine; D014700:Verapamil