Article: article from journal or magazin.
MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping.
Journal of Biological Chemistry
The human MDR3 gene is a member of the multidrug resistance (MDR) gene family. The MDR3 P-glycoprotein is a transmembrane protein that translocates phosphatidylcholine. The MDR1 P-glycoprotein related transports cytotoxic drugs. Its overexpression can make cells resistant to a variety of drugs. Attempts to show that MDR3 P-glycoprotein can cause MDR have been unsuccessful thus far. Here, we report an increased directional transport of several MDR1 P-glycoprotein substrates, such as digoxin, paclitaxel, and vinblastine, through polarized monolayers of MDR3-transfected cells. Transport of other good MDR1 P-glycoprotein substrates, including cyclosporin A and dexamethasone, was not detectably increased. MDR3 P-glycoprotein-dependent transport of a short-chain phosphatidylcholine analog and drugs was inhibited by several MDR reversal agents and other drugs, indicating an interaction between these compounds and MDR3 P-gp. Insect cell membranes from Sf9 cells overexpressing MDR3 showed specific MgATP binding and a vanadate-dependent, N-ethylmaleimide-sensitive nucleotide trapping activity, visualized by covalent binding with [alpha-(32)P]8-azido-ATP. Nucleotide trapping was (nearly) abolished by paclitaxel, vinblastine, and the MDR reversal agents verapamil, cyclosporin A, and PSC 833. We conclude that MDR3 P-glycoprotein can bind and transport a subset of MDR1 P-glycoprotein substrates. The rate of MDR3 P-glycoprotein-mediated transport is low for most drugs, explaining why this protein is not detectably involved in multidrug resistance. It remains possible, however, that drug binding to MDR3 P-glycoprotein could adversely affect phospholipid or toxin secretion under conditions of stress (e.g. in pregnant heterozygotes with one MDR3 null allele).
ATP-Binding Cassette Transporters/genetics, ATP-Binding Cassette Transporters/metabolism, Adenosine Triphosphate/metabolism, Animals, Biological Transport/drug effects, Cell Polarity, Cells, Cultured, Cyclosporine/pharmacology, Cyclosporins/pharmacology, Cytotoxins/metabolism, Daunorubicin/metabolism, Digoxin/metabolism, Epithelial Cells/cytology, Humans, Ivermectin/metabolism, Kidney/cytology, P-Glycoproteins/genetics, P-Glycoproteins/metabolism, Paclitaxel/metabolism, Pharmaceutical Preparations/metabolism, Phosphatidylcholines/metabolism, Recombinant Proteins/metabolism, Spodoptera/cytology, Swine, Verapamil/pharmacology, Vinblastine/metabolism
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