Involvement of Rat Organic Anion Transporter 3 in the Uptake of an Organic Herbicide, 2,4-Dichlorophenoxyacetate, by the isOlated Rat Choroid Plexus

Autor: Yoshinori Nagata, Hiroyuki Kusuhara, Yuichi Sugiyama, Hitoshi Endou, Tomoki Imaoka
Rok vydání: 2004
Předmět:
Zdroj: Journal of Pharmaceutical Sciences. 93:2724-2732
ISSN: 0022-3549
Popis: 2,4-Dichlorophenoxyacetic acid (2,4-D) is an anionic herbicide. The purpose of the present study is to examine whether organic anion transporter 3 (Oat3; Slc22a8) is solely responsible for the uptake of 2,4-D by the isolated rat choroid plexus (CP). When expressed in LLC-PK1 cells, rOat3 was mainly localized to the basolateral membrane. Although there was no vectorial transport of 2,4-D in the control LLC-PK1 cells, expression of rOat3 increased the basal-to-apical transport of 2,4-D fourfold without affecting the transcellular transport in the opposite direction. The basal-to-apical transport of 2,4-D in rOat3-LLC was saturable with a Km value of 20 μM. The uptake of 2,4-D by the isolated rat CP was determined using the centrifugal filtration method. Saturable uptake of 2,4-D was observed in the isolated rat CP with a Km value of 22 μM. Probenecid and substrates of rOat3, such as p-aminohippurate, benzylpenicillin, and cimetidine, inhibited the uptake of 2,4-D by the isolated rat CP. Their Ki values were comparable with those for the uptake of benzylpenicillin by the isolated rat CP, which is mainly mediated by rOat3. Furthermore, benzylpenicillin was a competitive inhibitor for the uptake of 2,4-D by the isolated rat CP. These results suggest that 2,4-D and benzylpenicillin share the same transporter for their uptake by the isolated rat CP, and rOat3 is the most likely candidate transporter. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2724–2732, 2004
Databáze: OpenAIRE
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