PT - JOURNAL ARTICLE AU - MeeRa Hong AU - Lyanne Schlichter AU - Reina Bendayan TI - A Novel Zidovudine Uptake System in Microglia DP - 2001 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 141--149 VI - 296 IP - 1 4099 - http://jpet.aspetjournals.org/content/296/1/141.short 4100 - http://jpet.aspetjournals.org/content/296/1/141.full SO - J Pharmacol Exp Ther2001 Jan 01; 296 AB - 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, andN1-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. The American Society for Pharmacology and Experimental Therapeutics