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Vol. 292, Issue 1, 366-374, January 2000

A Na+-Dependent Nucleoside Transporter in Microglia1

MeeRa Hong2 3, Lyanne Schlichter4 and Reina Bendayan2

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

In the central nervous system, HIV-1 has a defined tropism for brain macrophages and microglia. Nucleoside analog drugs such as zidovudine improve the clinical and neuropsychological functions in HIV-demented patients. Multiple carrier-mediated transport systems can play an important role in the membrane permeation of nucleosides and nucleoside analog drugs in a number of cells. The purpose of this project was to characterize the uptake properties of the pyrimidine nucleoside probe thymidine by a continuous rat microglia cell line (MLS-9) grown as a monolayer on an impermeable substratum. Approximately 50% of thymidine (10 µM) uptake by the monolayer cells was found to be Na+ dependent. Kinetics of specific thymidine uptake showed a single saturation system (Km = 44 µM at 37°C) and a Na+/thymidine stoichiometry of 2:1. Pyrimidine and purine nucleoside probes (50 µM) exerted a competitive inhibitory effect on specific thymidine uptake with Ki values of 40, 38, 45, and 39 µM for adenosine, uridine, guanosine, and cytidine, respectively. In addition, nucleoside analog drugs significantly decreased specific thymidine uptake, with IC50 values of 135.1 µM for abacavir and 0.6 µM for zidovudine, which inhibited in a noncompetitive manner. These results suggest that a Na+-dependent nucleoside transport system is present in rat microglia and that long-range interactions between antiretroviral nucleoside analog drugs and the nucleoside substrates may occur at the transporter sites.

1 This work is supported by a grant from the Ontario HIV Treatment Network, the Canadian Foundation for AIDS Research, and the Medical Research Council (MT-13657). M. Hong is a recipient of an Ontario HIV Treatment Network Studentship Award.

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

3 M. Hong, P. Pennefather, L. Schlichter, and R. Bendayan. Transport properties of thymidine by a rat microglia cell line. Abstract selected for presentation at the 100th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Antonio, TX, March 1999.

4 Current address: The Neuroscience Institute, University Health Network, Toronto, Ontario M5T 2S8 and Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A1, Canada.

0022-3565/0/2921-0366$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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