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PMID:12893836

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Citation

Dallas, S, Zhu, X, Baruchel, S, Schlichter, L and Bendayan, R (2003) Functional expression of the multidrug resistance protein 1 in microglia. J. Pharmacol. Exp. Ther. 307:282-90

Abstract

Brain expression of the multidrug resistance proteins (MRPs), a collection of membrane-associated ATP-dependent efflux transporters, is poorly understood. Although several studies have examined the expression of these proteins within the brain barriers (i.e., the blood-brain barrier and choroid plexus), little information is available with respect to brain parenchyma cells such as microglia and astrocytes. Because microglia are the primary brain cells infected by the human immunodeficiency virus type 1 (HIV-1), MRP1 expression within microglia may contribute to lower brain accumulation of anti-HIV drugs. To examine the expression pattern of MRP1 within microglia, we performed reverse transcriptase-polymerase chain reaction analysis and Western blotting on a rat brain microglia cell line MLS-9, and in primary cultures of rat microglia. Both rat MRP1 (rMPR1) mRNA and protein were expressed in the cell line, as well as the primary cultures. We then characterized rMRP1-mediated transport properties in MLS-9 cells using [3H]vincristine, a known MRP1 substrate. Vincristine accumulation by monolayers of MLS-9 cells increased significantly in the presence of several well established MRP1 inhibitors (MK571, genistein, sulfinpyrazone, probenecid, and indomethacin), protease inhibitors, or the ATPase inhibitor sodium azide. In addition, vincristine accumulation was significantly modulated by altering the intracellular concentration of the reduced form of glutathione, further suggesting the involvement of rMRP1-mediated transport. These results provide strong evidence that the MRP1 protein is both expressed and functional in microglia cells. They also suggest that brain parenchyma can act as a "second" barrier to drug permeability and regulate brain distribution/accumulation of various xenobiotics, including protease inhibitors.

Links

PubMed Online version:10.1124/jpet.103.054304

Keywords

Animals; Biological Transport; Cells, Cultured; Humans; Microglia/metabolism; P-Glycoprotein/biosynthesis; P-Glycoprotein/genetics; RNA, Messenger/biosynthesis; Rats; Rats, Wistar; Time Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:MRP1

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MRP1

enables

GO:0008559: ABC-type xenobiotic transporter activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MRP1

enables

GO:0008559: xenobiotic transmembrane transporting ATPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MRP1

part_of

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MRP1

involved_in

GO:0042908: xenobiotic transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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