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Received for publication December 8, 2003.
Revised January 20, 2004.
Accepted for publication February 2, 2004.
The pathogenesis of Human immunodeficiency virus-associated dementia has been linked to microglial responses following infection. We have recently confirmed expression of several ATP-dependent efflux transporters in microglia, namely multidrug-resistance protein 1 (MRP1) and P-glycoprotein (P-gp). In the present study, we investigated whether cultured rat microglia express two additional MRP family members, rMRP4 and rMRP5. Using reverse transcriptase-polymerase chain reaction, rMRP4 and rMRP5 mRNA was detected in primary cultures of microglia and in a rat microglia cell line, MLS-9. Western blot analysis further confirmed protein expression of the two MRP isoforms in MLS-9 cells. Bis(pivaloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine [bis(POM)PMEA], a lipophilic ester pro-drug of the well-characterized MRP4 and 5 substrate 9-(2-phosphonylmethoxyethyl)adenine (PMEA), was chosen to examine transport characteristics in MLS-9. Using Thin Layer Chromatography, we verified that more than 90% of radioactivity recovered in MLS-9 loaded with 1 µM [3H]bis(POM)PMEA for 1 hr under ATP depleting conditions was converted to PMEA. Efflux of PMEA by MLS-9 cell monolayers was ATP-dependent, glutathione-independent and significantly inhibited by several MRP inhibitors (i.e., sulfinpyrazone, genistein, indomethacin, probenecid) as well as the antiretroviral drug azidothymidine-monophosphate. Similar results were not observed in MRP1 or P-gp overexpressing cell lines suggesting that PMEA is not a substrate for either P-gp or MRP1. These studies provide further evidence that microglia express multiple subfamilies of ATP-Binding Cassette transporters (i.e., P-gp, MRP1, MRP4, MRP5) that could restrict permeation of several different classes of antiretroviral drugs in a brain cellular target of HIV-1 infection.
Key words:
Antiretroviral, Brain, Human Immunodeficiency Virus-1, Microglia, Multidrug Resistance Proteins, Transport
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