Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat.
Our previous kinetic analyses have shown that rat organic anion transporter 1 (rOat1; Slc22a6) and rOat3 (Slc22a8) are responsible for the renal uptake of p-aminohippurate and pravastatin, respectively. In this study, their contribution to the renal uptake of organic anions and nucleoside derivatives was examined by investigating the uptake by rOat1- and rOat3-expressing cells and kidney slices. Transfection of rOat1 resulted in an increase of the uptake of temocaprilat (Km = 0.56 microM), 2,4-dichlorophenoxyacetate (2,4-D; Km = 10 microM), and 3'-azido-3'-deoxythymidine (AZT; Km = 43 microM). rOat3-expressing cells showed significant uptake of temocaprilat (Km = 1.4 microM), estrone sulfate (Km = 5.3 microM), dehydroepiandrosterone sulfate (DHEAS; Km = 12 microM), and benzylpenicillin (PCG; Km = 85 microM). All the test compounds were accumulated in kidney slices in a carrier-mediated manner, although the saturable components of AZT and acyclovir were small. The Km of 2,4-D uptake by kidney slices was comparable with that of rOat1, and the corresponding values of DHEAS and PCG were similar to those of rOat3. The uptake of estrone sulfate and temocaprilat by kidney slices consisted of two saturable components, with the Km values of their high-affinity components being similar to those for rOat3 (estrone sulfate), and rOat1 and rOat3 (temocaprilat), respectively. These results suggest that the renal uptake of 2,4-D is mainly accounted for by rOat1 and the uptake of PCG and DHEAS by rOat3, and rOat3 is partly involved in the renal uptake of temocaprilat and estrone sulfate.
Hasegawa
Maki
M
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kusuhara
Hiroyuki
H
Endou
Hitoshi
H
Sugiyama
Yuichi
Y
D000818:Animals; D000838:Anions / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport; D018076:DNA, Complementary / Q000235:genetics; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D000838:Anions; D018076:DNA, Complementary; D009705:Nucleosides; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3