Polychlorinated biphenyls are not substrates for the multidrug resistance transporter-1.
The multidrug resistance (MDR) transporter is a phosphorylated glycoprotein (P-gp) that has been implicated in the efflux of a large variety of xenobiotics, thereby protecting vital organs. This study examines the hypothesis that the multidrug resistance transporter is involved in restricting the entry of polychlorinated biphenyls (PCBs) into the brain. Three test systems were used. First, the ATPase activity of the human P-gp was measured as an indicator of the interaction of PCBs with the MDR transporter. PCB congeners and metabolites included in the study were PCB 153, PCB 169, PCB 77, and the 4-hydroxy and 4,4'-dihydroxy metabolites of PCB 77. An increase in ATPase activity was observed for all the PCBs tested except the 4-hydroxy metabolite of PCB 77. Second, we studied the transport of (14)C-PCB 77 and (14)C-PCB153 in a cell-culture model using porcine kidney cells expressing the human MDR1 or the mouse mdr1a gene and compared it to the transport in control cells. No difference in directional transport due to P-gp was observed with either of the congeners in any of the cell lines. Finally, the distribution pattern of (14)C-PCB 77 in mdr1a knockout mice and genetically matched wild-type mice was measured. No significant differences in tissue distribution, especially in the brain tissue, were observed between wild-type and mdr1a knockout mice. These results suggest that some PCB congeners can bind to the MDR1 transporter; however, they may not be transported by it.
Tampal
Nilufer M
NM
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA.
Robertson
Larry W
LW
Srinivasan
Cidambi
C
Ludewig
Gabriele
G
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D013379:Substrate Specificity; D013552:Swine; D013997:Time Factors
D000251:Adenosine Triphosphatases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011078:Polychlorinated Biphenyls; C421109:multidrug resistance-associated protein 1