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Vol. 296, Issue 1, 141-149, January 2001

A Novel Zidovudine Uptake System in Microglia

MeeRa Hong1, Lyanne Schlichter2 and Reina Bendayan1

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

In the central nervous system (CNS), brain macrophages and microglia are the primary targets of productive human immunodeficiency virus 1 (HIV-1) infection. Zidovudine (ZDV), a thymidine derivative, has been reported to reduce the progression of the disease and prolong survival in patients with acquired immunodeficiency syndrome (AIDS) and AIDS dementia complex. Although a restricted ZDV distribution has been observed in the CNS, its accumulation in brain parenchyma has not been examined. We have investigated the uptake properties of radiolabeled ZDV by a continuous rat microglia cell line (MLS-9) grown as a monolayer on an impermeable surface. Although the organic cations verapamil, mepiperphenidol, quinidine, cimetidine, and N1-methylnicotinamide moderately inhibited ZDV uptake, the organic cation probes tetraethylammonium and 1-methyl-4-phenylpyridinium were weak inhibitors. ZDV uptake was significantly increased when the proton gradient was outward (pHi 6.3 < pHo 7.4; pHi ~7.1 < pH 8.0), whereas uptake decreased with extracellular acidification (pHi ~7.1 > pHo 6.0) or in the presence of the Na+/H+ ionophore monensin. ZDV uptake was increased under depolarized membrane conditions (i.e., 138 mM K+ in external medium) and decreased under hyperpolarized conditions (i.e., 2 mM K+ in external medium), implying a membrane potential dependence. These results suggest that although ZDV transport system in microglia has some specificity features of an organic cation transporter, it involves a carrier, distinct from other cloned organic cation transporters, that is novel in its sensitivity to pH and membrane potential. This system may play a significant role in the transport of other weak organic cation substrates and/or metabolites in brain parenchyma.

1 Current address: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 2S2, Canada.

2 Current address: Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8 and Department of Physiology and Institute for Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A1, Canada.

0022-3565/01/2961-0141$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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