Role of organic cation transporters in the renal secretion of nucleosides

The mammalian kidney eliminates toxic substances from the body, in part via secretion by the organic cation transporters (OCT) or organic anion transp orters. Nucleosides are nitrogenous heterocycles that are often secreted by human and other animal kidneys. Previous experiments have shown that 2'-de oxytubercidin (7-deazadeoxyadenosine, dTub) is secreted by the mouse kidney via a cimetidine-sensitive OCT (Nelson et al., Biochem Pharmacol 32: 2323- 2327, 1983). Experiments reported herein demonstrated that the cloned rat k idney rOCT1 transports dTub, cytosine arabinoside, 2-chlorodeoxyadenosine, and azidothymidine when expressed in the Xenopus laevis oocyte translation system. Although rOCT2 is 67% identical with rOCT1 in its amino acid sequen ce, rOCT2 does not mediate the uptake of these nucleosides. Uptake of dTub mediated by rOCT1 was pH dependent in a manner suggesting that the positive charged moiety of dTub may be the true substrate. Protons acted as competi tive inhibitors for the rOCT1-mediated uptake of dTub or tetraethylammonium (TEA), with K-i values corresponding to a pH of about 6.1. TEA and dTub mu tually inhibited the uptake of one another by rOCT1, competitively, with Ki values approximately the same as their respective K-m values. These findin gs suggest that protons, dTub, and TEA act at a common site on rOCT1, and t hat rOCT1 participates in the renal secretion of dTub and other nucleosides . (C) 2000 Elsevier Science Inc.