Polychlorinated biphenyls are not substrates for the multidrug resistance transporter-1

Nilufer M. Tampal; Larry W. Robertson; Cidambi Srinivasan; Gabriele Ludewig

doi:10.1016/S0041-008X(02)00069-8

Polychlorinated biphenyls are not substrates for the multidrug resistance transporter-1

Nilufer M. Tampal, Larry W. Robertson, Cidambi Srinivasan, Gabriele Ludewig

Dr. Bing Zhang Department of Statistics

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

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 ¹⁴C-PCB 77 and ¹⁴C-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 ¹⁴C-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.

Original language	English
Pages (from-to)	168-177
Number of pages	10
Journal	Toxicology and Applied Pharmacology
Volume	187
Issue number	3
DOIs	https://doi.org/10.1016/S0041-008X(02)00069-8
State	Published - Mar 15 2003

Bibliographical note

Funding Information:
The authors gratefully acknowledge Dr. Mary Vore (Graduate Center for Toxicology) for advice and helpful discussions. We also thank Dr. H.-J. Lehmler, Dr. P. Espandiari, Dr. T. Twaroski, Dr. A. Srinivasan, D. Stemm, and M. Festag for help with animal treatment and tissue collection. This publication was made possible by Grant DAMD 17-02-1-0241 from the DOD, Grant R-82902101-0 from the EPA, Grant P42 ES 07380 from NIEHS, and Grant 85-001-13-IRG from the American Cancer Society. N.M.T. was supported in part by a training grant from the Superfund Basic Research Program (ES-07380). Contents are solely the responsibility of the authors and do not necessarily represent the official views of the ACS, DOD, EPA, NIEHS, or NIH. Portions of this paper were presented at the 40th Annual Meeting of the Society of Toxicology held March 2001, in San Francisco, CA, and published in Toxicologist, 60, Abstract 1829.

Keywords

ATPase
Blood brain barrier
MDR
PCB77
Polychlorinated biphenyls
Transport
mdr1a knock-out mice

ASJC Scopus subject areas

Toxicology
Pharmacology

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10.1016/S0041-008X(02)00069-8

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abstract = "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 14C-PCB 77 and 14C-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 14C-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.",

keywords = "ATPase, Blood brain barrier, MDR, PCB77, Polychlorinated biphenyls, Transport, mdr1a knock-out mice",

author = "Tampal, {Nilufer M.} and Robertson, {Larry W.} and Cidambi Srinivasan and Gabriele Ludewig",

note = "Funding Information: The authors gratefully acknowledge Dr. Mary Vore (Graduate Center for Toxicology) for advice and helpful discussions. We also thank Dr. H.-J. Lehmler, Dr. P. Espandiari, Dr. T. Twaroski, Dr. A. Srinivasan, D. Stemm, and M. Festag for help with animal treatment and tissue collection. This publication was made possible by Grant DAMD 17-02-1-0241 from the DOD, Grant R-82902101-0 from the EPA, Grant P42 ES 07380 from NIEHS, and Grant 85-001-13-IRG from the American Cancer Society. N.M.T. was supported in part by a training grant from the Superfund Basic Research Program (ES-07380). Contents are solely the responsibility of the authors and do not necessarily represent the official views of the ACS, DOD, EPA, NIEHS, or NIH. Portions of this paper were presented at the 40th Annual Meeting of the Society of Toxicology held March 2001, in San Francisco, CA, and published in Toxicologist, 60, Abstract 1829.",

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Polychlorinated biphenyls are not substrates for the multidrug resistance transporter-1

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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