A novel zidovudine uptake system in microglia.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 01/2001; 296(1):141-9.
Source: PubMed


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.

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Available from: Lyanne C Schlichter, Mar 03, 2015
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    • "Our previous findings that hOATs are not expressed in immune cells are particularly interesting (Purcet et al., 2006). As for human organic cation transporters (hOCTs), no specific member has been described yet as an NRTI transporter in immune cells, even though it has been suggested an organic cation transport for AZT and 3TC uptake in microglia and the renal brush-border membrane, respectively (Takubo et al., 2000a; Hong et al., 2001). Because we had found previously that hOCTs are well expressed and functionally active in immune cells and highly up-regulated after activation of CD4 T cells (Minuesa et al., 2008), we were interested in studying the role of hOCTs in the uptake of NRTIs, the possible cross-inhibition between them, and whether these drugs interact and, therefore, inhibit the physiological function of hOCTs. "
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