TY - JOUR
T1 - Role of organic cation transporters in the renal secretion of nucleosides
AU - Chen, Rong
AU - Nelson, J. Arly
N1 - Funding Information:
We thank Dr. William P. Dubinsky, Dr. V. Ganapathy, and Dr. John B. Pritchard for their critical review of the manuscript and provision of the materials. Ms. Bih-fang Pan and Ms. Rosalind Alexander provided excellent assistance. This work was supported by National Institutes of Health Grants DK41606, Institute for Digestive Diseases and Kidney, and 2-P30-CA16672, a National Cancer Center Core Grant.
PY - 2000/7/15
Y1 - 2000/7/15
N2 - The mammalian kidney eliminates toxic substances from the body, in part via secretion by the organic cation transporters (OCT) or organic anion transporters. Nucleosides are nitrogenous heterocycles that are often secreted by human and other animal kidneys. Previous experiments have shown that 2'-deoxytubercidin (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 kidney 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 sequence, 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 competitive 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 mutually inhibited the uptake of one another by rOCT1, competitively, with K(i) values approximately the same as their respective K(m) values. These findings suggest that protons, dTub, and TEA act at a common site on rOCT1, and that rOCT1 participates in the renal secretion of dTub and other nucleosides. Copyright (C) 2000 Elsevier Science Inc.
AB - The mammalian kidney eliminates toxic substances from the body, in part via secretion by the organic cation transporters (OCT) or organic anion transporters. Nucleosides are nitrogenous heterocycles that are often secreted by human and other animal kidneys. Previous experiments have shown that 2'-deoxytubercidin (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 kidney 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 sequence, 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 competitive 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 mutually inhibited the uptake of one another by rOCT1, competitively, with K(i) values approximately the same as their respective K(m) values. These findings suggest that protons, dTub, and TEA act at a common site on rOCT1, and that rOCT1 participates in the renal secretion of dTub and other nucleosides. Copyright (C) 2000 Elsevier Science Inc.
KW - AZT
KW - Nucleosides
KW - Organic cation
KW - Renal clearance
KW - TEA
KW - Transport
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U2 - 10.1016/S0006-2952(00)00334-8
DO - 10.1016/S0006-2952(00)00334-8
M3 - Article
C2 - 10825466
AN - SCOPUS:0034662431
SN - 0006-2952
VL - 60
SP - 215
EP - 219
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -