A novel zidovudine uptake system in microglia.

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 N(1)-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 (pH(i) 6.3 < pH(o) 7.4; pH(i) approximately 7.1 < pH 8.0), whereas uptake decreased with extracellular acidification (pH(i) approximately 7.1 > pH(o) 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.