Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier.
The present study was aimed at investigating the involvement of mouse organic anion transporting polypeptide 14 (mOatp14) in the uptake of T4 across the blood-brain barrier. Functional expression of mOatp14 in HEK293 cells revealed that T4 and rT3 are high affinity substrates of mOatp14 (Michaelis constant, 0.34 and 0.46 microm, respectively), and the specific uptake of T3 was 4-fold less than that of T4 and rT3. Taurocholate, probenecid, and estrone-3-sulfate were moderate inhibitors for mOatp14, whereas digoxin (substrate of Oatp2), benzylpenicillin (substrate of Oat3), and large neutral amino acids had no effect. mOatp14 is widely expressed throughout the brain, except for the cerebellum. The expression of mOatp14 in the isolated brain capillaries and the choroid plexus was shown by Western blot. The uptake clearance of T4 by the cerebral cortex determined using the in situ brain perfusion technique in mice was 580 microl/min.g tissue, 3-fold greater than that by the cerebellum, and a saturable component (Michaelis constant, 1.0 microm) accounts for the major fraction of the total uptake. Taurocholate inhibited the uptake of T4 by the cerebral cortex completely, but the inhibition by estrone-3-sulfate was partial (50%). These results suggest that transporters play a predominant role in the delivery of T4 to the brain, and mOatp14 accounts for estrone-3-sulfate inhibitable fraction, at least partly. The absence of inhibition by digoxin, benzylpenicillin, leucine, and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid for the uptake of T4 by the cerebral cortex suggests the presence of other unknown transporter for T4 uptake by the brain. Immunohistochemical staining revealed basolateral localization of mOatp14 in the choroid plexus in which it may also play a role in T4 uptake.
Tohyama
Kimio
K
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kusuhara
Hiroyuki
H
Sugiyama
Yuichi
Y
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D002531:Cerebellum / Q000098:blood supply; D002540:Cerebral Cortex / Q000098:blood supply; D002831:Choroid Plexus / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D013974:Thyroxine / Q000493:pharmacokinetics*; D014284:Triiodothyronine / Q000493:pharmacokinetics
D007457:Iodine Radioisotopes; C464433:Oatp2 protein, mouse; D027701:Organic Cation Transport Proteins; D014284:Triiodothyronine; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D013974:Thyroxine