title: Involvement of rat organic anion transporter 3 in the uptake of an organic herbicide, 2,4-dichlorophenoxyacetate, by the isolated rat choroid plexus.
abstract: 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 K(m) value of 20 microM. 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 K(m) value of 22 microM. 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 K(i) 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.
authors.affiliation: Graduate school of Pharmaceutical Sciences, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Tomoki
authors.initials: T
authors.lastname: Imaoka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D015084:2,4-Dichlorophenoxyacetic Acid / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002831:Choroid Plexus / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: D006540:Herbicides; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D015084:2,4-Dichlorophenoxyacetic Acid