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Interactions of Nucleoside Analogs, Caffeine, and Nicotine with Human Concentrative Nucleoside Transporters 1 and 2 Stably Produced in a Transport-Defective Human Cell Line

From the Canadian Institutes of Health Research Molecular Biology of Membranes Group (T.T.L., J.D.Y., C.E.C.), Departments of Oncology (T.T.L., C.E.C.) and Physiology (J.D.Y.), University of Alberta, Edmonton, Alberta, Canada; and the Cross Cancer Institute, Edmonton, Alberta, Canada (T.T.L., C.E.C.)

Pharmacologically important drugs were examined as potential inhibitors or permeants of human concentrative nucleoside transporters 1 (hCNT1)- and 2 (hCNT2)-producing stable transfectants by assessing their abilities to inhibit uridine transport. hCNT1 exhibited high affinities for uridine analogs (5-fluorouridine, 2'-deoxyuridine, 5-fluoro-2'-deoxyuridine, and 5-fluoro-5'-deoxyuridine) with K_i values of 22 to 33 µM, whereas hCNT2 exhibited moderate affinities for 5-fluoro-2'-deoxyuridine, high affinities for 2'-deoxyuridine and 5-fluorouridine, and low affinity for 5-fluoro-5'-deoxyuridine. The uridine analogs were transported at 2-fold higher rates (at 10 µM) by hCNT1 than by hCNT2. Enantiomeric configuration and the 3'-hydroxyl group of the ribose ring were important determinants for interaction with hCNTs, whereas the 2'-hydroxyl group was less important. Both transporters bound N⁶-(p-aminobenzyl)adenosine with affinities similar to those of adenosine (K_i = 28-39 µM). Other adenosine receptor ligands, including caffeine, bound better to hCNT1 than to hCNT2 (K_i = 46 versus 103 µM, respectively), whereas 2-chloroadenosine bound better to hCNT2 than to hCNT1 (K_i = 37 and 101 µM, respectively). There was a greater than 3-fold difference in binding affinities between hCNT1 and hCNT2 for nicotine (K_i = 63 versus 227 µM). However, direct measurements of nicotine and caffeine uptake rates (10 µM) failed to demonstrate mediated uptake by either transporter. Although hCNT1 bound several adenosine analogs relatively well, it did not transport 2-chloro-2'-deoxyadenosine (cladribine) or 2-fluoro-9--D-arabinofuranosyladenine (fludarabine), whereas hCNT2 transported both, albeit with low activities. The results indicated that although hCNT1 and hCNT2 possess some overlap in transport of several uridine and adenosine analogs, they also exhibit distinct differences in capacity to interact with some adenosine receptor ligands, adenosine-based drugs, and nicotine.

Received August 27, 2003; accepted December 22, 2003.

Address correspondence to: Dr. Carol Cass, Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2 Canada. E-mail: carol.cass{at}cancerboard.ab.ca

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