BILE CANALICULAR CATIONIC DYE SECRETION AS A MODEL FOR P-GLYCOPROTEINMEDIATED TRANSPORT

This study explores properties of P-glycoprotein dependent membrane tr ansport in rat liver with the use of acridine orange as the substrate. We studied the biliary secretion of the dye, its binding to canalicul ar membrane P-glycoprotein, and effects of the inhibitor cyclosporin A : acridine orange is excreted into bile together with less hydrophobic and glucuronidated metabolites. Cyclosporin A inhibited both the secr etion of acridine orange and of its metabolites. In TR(-) animals, a r at strain that is deficient of the canalicular multi-specific organic anion transport system, non-metabolized acridine orange is the predomi nant species in bile and its secretion is also inhibited by cyclospori n A, Binding of acridine orange to liver P-glycoprotein was analyzed b y photoaffinity labeling with azidopine, a substrate of P-glycoprotein dependent transport in multi-drug resistant tumor cells. Labeling of the immunoprecipitated P-glycoprotein was inhibited by acridine orange , verapamil, and by cyclosporin A. The results show that biliary secre tion of acridine orange is highly analogous to P-glycoprotein mediated membrane drug transport in tumor cells that exhibit multi-drug resist ance.