Functional Characterization of Rat Brain-specific Organic Anion Transporter (Oatp14) at the Blood-Brain BarrierOatp14/blood-brain barrier-specific anion transporter 1 (Slc21a14) is a novel member of the organic anion transporting polypeptide (Oatp/OATP) family. Northern blot analysis revealed predominant expression of Oatp14 in the brain, and Western blot analysis revealed its expression in the brain capillary and choroid plexus. Immunohistochemical staining indicated that Oatp14 is expressed in the border of the brain capillary endothelial cells. When expressed in human embryonic kidney 293 cells, Oatp14 transports thyroxine (T4; prothyroid hormone) (Km = 0.18 μm), as well as amphipathic organic anions such as 17β estradiol-d-17β-glucuronide (Km = 10 μm), cerivastatin (Km = 1.3 μm), and troglitazone sulfate (Km = 0.76 μm). The uptake of triiodothyronine (T3), an active form produced from T4, was significantly greater in Oatp14-expressed cells than in vector-transfected cells, but the transport activity for T3 was ∼6-fold lower that for T4. The efflux of T4, preloaded into the cells, from Oatp14-expressed cells was more rapid than that from vector-transfected cells (0.032 versus 0.006 min–1). Therefore, Oatp14 can mediate a bidirectional transport of T4. Sulfobromophthalein, taurocholate, and estrone sulfate were potent inhibitors for Oatp14, whereas digoxin, p-aminohippurate, or leukotriene C4, or organic cations such as tetraetheylammonium or cimetidine had no effect. The expression levels of Oatp14 mRNA and protein were up- and down-regulated under hypo- and hyperthyroid conditions, respectively. Therefore, it may be speculated that Oatp14 plays a role in maintaining the concentration of T4 and, ultimately, T3 in the brain by transporting T4 from the circulating blood to the brain. Oatp14/blood-brain barrier-specific anion transporter 1 (Slc21a14) is a novel member of the organic anion transporting polypeptide (Oatp/OATP) family. Northern blot analysis revealed predominant expression of Oatp14 in the brain, and Western blot analysis revealed its expression in the brain capillary and choroid plexus. Immunohistochemical staining indicated that Oatp14 is expressed in the border of the brain capillary endothelial cells. When expressed in human embryonic kidney 293 cells, Oatp14 transports thyroxine (T4; prothyroid hormone) (Km = 0.18 μm), as well as amphipathic organic anions such as 17β estradiol-d-17β-glucuronide (Km = 10 μm), cerivastatin (Km = 1.3 μm), and troglitazone sulfate (Km = 0.76 μm). The uptake of triiodothyronine (T3), an active form produced from T4, was significantly greater in Oatp14-expressed cells than in vector-transfected cells, but the transport activity for T3 was ∼6-fold lower that for T4. The efflux of T4, preloaded into the cells, from Oatp14-expressed cells was more rapid than that from vector-transfected cells (0.032 versus 0.006 min–1). Therefore, Oatp14 can mediate a bidirectional transport of T4. Sulfobromophthalein, taurocholate, and estrone sulfate were potent inhibitors for Oatp14, whereas digoxin, p-aminohippurate, or leukotriene C4, or organic cations such as tetraetheylammonium or cimetidine had no effect. The expression levels of Oatp14 mRNA and protein were up- and down-regulated under hypo- and hyperthyroid conditions, respectively. Therefore, it may be speculated that Oatp14 plays a role in maintaining the concentration of T4 and, ultimately, T3 in the brain by transporting T4 from the circulating blood to the brain. Brain capillary endothelial cells are characterized by tightly sealed cellular junctions (tight junctions) and the paucity of fenestra and pinocytotic vesicles, which prevent free exchange between brain and blood (1Rapoport S.I. Exp. Neurol. 1976; 52: 467-479Crossref PubMed Scopus (80) Google Scholar, 2Pardridge W.M. Semin. Cell Biol. 1991; 2: 419-426PubMed Google Scholar). Therefore, the uptake of nutrients by the brain occurs through the brain capillary endothelial cells via specific transport systems (3Minn A. Ghersi-Egea J.F. Perrin R. Leininger B. Siest G. Brain Res. Brain Res. Rev. 1991; 16: 65-82Crossref PubMed Scopus (157) Google Scholar, 4Strazielle N. Ghersi-Egea J.F. J. Neurosci. 1999; 15: 6275-6289Crossref Google Scholar, 5Suzuki H. Terasaki T. Sugiyama Y. Adv. Drug. Deliv. Rev. 1997; 25: 257-285Crossref Scopus (78) Google Scholar, 6Kusuhara H. Sugiyama Y. Drug Discov. Today. 2001; 6: 150-156Crossref PubMed Scopus (155) Google Scholar, 7Lee G. Dallas M. Hong M. Bendayan R. Pharmacol. Rev. 2001; 52: 569-596Crossref Scopus (249) Google Scholar). Metabolic enzymes and efflux transporters expressed in the brain capillaries facilitate the elimination of endogenous wastes and xenobiotics from the brain, and restrict their brain accumulation (3Minn A. Ghersi-Egea J.F. Perrin R. Leininger B. Siest G. Brain Res. Brain Res. Rev. 1991; 16: 65-82Crossref PubMed Scopus (157) Google Scholar, 4Strazielle N. Ghersi-Egea J.F. J. Neurosci. 1999; 15: 6275-6289Crossref Google Scholar, 5Suzuki H. Terasaki T. Sugiyama Y. Adv. Drug. Deliv. Rev. 1997; 25: 257-285Crossref Scopus (78) Google Scholar, 6Kusuhara H. Sugiyama Y. Drug Discov. Today. 2001; 6: 150-156Crossref PubMed Scopus (155) Google Scholar, 7Lee G. Dallas M. Hong M. Bendayan R. Pharmacol. Rev. 2001; 52: 569-596Crossref Scopus (249) Google Scholar). Because of these characteristics, the brain capillaries are referred to as the blood-brain barrier (BBB). 1The abbreviations used are: BBB, blood-brain barrier; Oatp, organic anion transporting polypeptide; BSAT, BBB-specific anion transporter; HEK293, human embryonic kidney 293; CA, cholate; GCA, glycocholate; LCA, lithocholate; CDCA, chenodeoxycholate; UDCA, ursodeoxycholate; PGD2, prostaglandin D2; PGE2, prostaglandin E2; E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; PBS, phosphate-buffered saline; DPDPE, [d-penicillamine2,5]-enkephalin; E217βG, 17β estradiol-d-17β-glucuronide; T4, thyroxine; TLCS, taurolithocholate sulfate; 4-MUS, 4-methylumbelliferone sulfate; TRO-S, troglitazone sulfate; RT, reverse transcriptase; MMI, methimazole; T3, triiodothyronine; ES, estrone sulfate; BSP, sulfobromophthalein; LT, leukotriene; D2, type 2 iodothyronine deiodinase. The organic anion transporting polypeptides (Oatps in rodents and OATPs in human) belong to the growing gene family of organic anion/prostaglandin transporters that can mediate sodium-independent membrane transport of numerous endogenous and xenobiotic amphipathic compounds (8Kullak-Ublick G.A. Stieger B. Hagenbuch B. Meier P.J. Semin. Liver Dis. 2000; 20: 273-292Crossref PubMed Scopus (240) Google Scholar, 9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar). Fourteen members of the Oatp/OATP gene family have been identified in rodents and humans, and they are classified within the gene superfamily of solute carriers as the Slc21a/SLC21A gene family (Human Gene Nomenclature Committee DataBase) (8Kullak-Ublick G.A. Stieger B. Hagenbuch B. Meier P.J. Semin. Liver Dis. 2000; 20: 273-292Crossref PubMed Scopus (240) Google Scholar, 9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar). Several members of the Oatp/OATP family have been identified in the brain (Oatp1–3 and moat1 in rodents and OATP-A in human) (10Jacquemin E. Hagenbuch B. Stieger B. Wolkoff A.W. Meier P.J. Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 133-137Crossref PubMed Scopus (550) Google Scholar, 11Noe B. Hagenbuch B. Stieger B. Meier P.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10346-11035Crossref PubMed Scopus (390) Google Scholar, 12Abe T. Kakyo M. Sakagami H. Tokui T. Nishio T. Tanemoto M. Nomura H. Hebert S.C. Matsuno S. Kondo H. Yawo H. J. Biol. Chem. 1998; 273: 22395-22401Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 13Nishio T. Adachi H. Nakagomi R. Tokui T. Sato E. Tanamoto M. Fujiwara K. Okabe M. Onogawa T. Suzuki T. Nakai D. Shiiba K. Suzuki M. Ohtani H. Kondo Y. Unno M. Ito S. Iinuma K. Nunoki K. Matsuno S. Abe T. Biochem. Biophys. Res. Commun. 2000; 275: 831-838Crossref PubMed Scopus (70) Google Scholar, 14Kullak-Ublick G.A. Hagenbuch B. Stieger B. Schteingart C.D. Hofmann A.F. Wolkoff A.W. Meier P.J. Gastroenterology. 1995; 109: 1274-1282Abstract Full Text PDF PubMed Scopus (373) Google Scholar). Especially, in the BBB, rat Oatp2 and human OATP-A have been shown to be expressed in the plasma membrane of the brain capillary endothelial cells (15Gao B. Stieger B. Noe B. Fritschy J.M. Meier P.J. J. Histochem. Cytochem. 1999; 47: 1255-1264Crossref PubMed Scopus (269) Google Scholar, 16Gao B. Hagenbuch B. Kullak-Ublick G.A. Benke D. Aguzzi A. Meier P.J. J. Pharmacol. Exp. Ther. 2000; 294: 73-79PubMed Google Scholar). Involvement of rat Oatp2 in the uptake and efflux transport of its substrates was investigated in vivo (17Dagenais C. Ducharme J. Pollack G.M. Neurosci. Lett. 2001; 301: 155-158Crossref PubMed Scopus (64) Google Scholar, 18Sugiyama D. Kusuhara H. Shitara Y. Abe T. Meier P.J. Sekine T. Endou H. Suzuki H. Sugiyama Y. J. Pharmacol. Exp. Ther. 2001; 298: 316-322PubMed Google Scholar). The uptake of [d-penicillamine2,5]-enkephalin (DPDPE) from the blood to the brain was determined by the brain perfusion technique in the presence and absence of Oatp2 inhibitors (17Dagenais C. Ducharme J. Pollack G.M. Neurosci. Lett. 2001; 301: 155-158Crossref PubMed Scopus (64) Google Scholar). The brain uptake of DPDPE was increased in Mdr1a (P-glycoprotein) gene knockout mice, and the uptake in Mdr1a knockout mice was inhibited by the substrates and inhibitors of rat Oatp2 such as digoxin and 17β estradiol-d-17β-glucuronide (E217βG). Vice versa, when E217βG was microinjected into the cerebral cortex, the subsequent elimination of E217βG from the brain was carrier-mediated (18Sugiyama D. Kusuhara H. Shitara Y. Abe T. Meier P.J. Sekine T. Endou H. Suzuki H. Sugiyama Y. J. Pharmacol. Exp. Ther. 2001; 298: 316-322PubMed Google Scholar), and the elimination of E217βG was completely inhibited by co-administration of taurocholate and probenecid, whereas digoxin had only a partial effect (18Sugiyama D. Kusuhara H. Shitara Y. Abe T. Meier P.J. Sekine T. Endou H. Suzuki H. Sugiyama Y. J. Pharmacol. Exp. Ther. 2001; 298: 316-322PubMed Google Scholar). Partial inhibition by digoxin suggested that additional efflux transport system(s) for E217βG, which is taurocholate- and probenecid-sensitive, is involved in the brain capillary. Li et al. (19Li J.Y. Boado R. Pardridge W.M. J. Cereb. Blood Flow Metab. 2001; 21: 61-68Crossref PubMed Scopus (126) Google Scholar) recently identified BBB-specific anion transporter 1 (BSAT1) using gene microarray techniques by comparing the gene expression profile of cDNA from the brain capillary with that from the liver and kidney. BSAT1 cDNA consisted of 2148 bp that encoded a 716-amino acid residues protein with 12 putative membrane-spanning domains. BSAT1 was highly enriched in the brain capillary compared with brain homogenate, liver, and kidney. Comparison of the cDNA sequences of BSAT1 revealed that it is the 14th member of the Oatp/OATP family (Oatp14). Although the localization at the BBB and the substrates of this isoform remain unknown, BBB-specific expression prompted us to hypothesize that Oatp14 accounts for the efflux of organic anions including E217βG via the BBB, together with Oatp2. The purpose of the present study is to characterize the substrate specificity and spectrum of inhibitors of Oatp14, as well as its tissue distribution and localization. Through this study, we found out that thyroxine (T4) is a good substrate of Oatp14, and the expression level of Oatp14 in the BBB is affected by plasma thyroid conditions. The results of the present study suggest that Oatp14 plays an important role in regulating the concentration of T4 in the central nervous system and in brain development. Chemicals—[3H]Leu-enkephalin was purchased from American Radiolabeled Chemicals (St. Louis, MO). [3H]Pravastatin was kindly donated from Sankyo (Tokyo, Japan), [14C]cerivastatin was from Bayer AG (Wuppertal, Germany), and [14C]E3040 glucuronide and [14C]E3040 sulfate were from Eisai (Tokyo, Japan). [3H]Taurolithocholate sulfate (TLCS), [35S]4-methylumbelliferone sulfate (4-MUS), and [35S]troglitazone sulfate (TRO-S) were synthesized according to a method described previously (20Izumi T. Hosiyama K. Enomoto S. Sasahara K. Sugiyama Y. J. Pharmacol. Exp. Ther. 1997; 280: 1392-40021PubMed Google Scholar, 21Akita H. Suzuki H. Ito K. Kinoshita S. Sato N. Takikawa H. Sugiyama Y. Biochim. Biophys. Acta. 2001; 1511: 7-16Crossref PubMed Scopus (173) Google Scholar). The radiochemical purity of [3H]TLCS, [35S]4-MUS, and [35S]TRO-S prepared by this method were more than 95%. Other labeled compounds were purchased from PerkinElmer Life Science. Unlabeled pravastatin, and its were kindly donated from cerivastatin was from Bayer and glucuronide and sulfate were from were of and were used brain capillaries were using a of the of Boado et al. Pardridge W.M. J. 1991; PubMed Scopus Google Scholar). in the were out at in of were in of an and, of concentration the was at The was in 10 and 1 and through a The was a of and with the capillaries to the were by Northern blot from rat Northern was used for the Northern blot from Oatp14 was used as a and its than with members of the family. The blot was with the at according to The was under = and and at and to for at and using an 2000; Western Oatp14 was in a of the of was by using the and used for subsequent brain homogenate, and brain capillary were with were for and an with a were a membrane using a at for 1 The membrane was with and for 1 at with the membrane was with the The membrane was to a in for 1 at by with Immunohistochemical from were prepared for the study in The brain to the were with and for 10 in with PBS, the capillaries were in in and with for 10 at to were with for at with PBS, and for at with the The was using and were with The specificity of the was by which were with that had been with the of Oatp14 the by Li et al. (19Li J.Y. Boado R. Pardridge W.M. J. Cereb. Blood Flow Metab. 2001; 21: 61-68Crossref PubMed Scopus (126) Google Scholar) the were to Oatp14 cDNA a of and reverse was using cDNA prepared from rat brain as according to the for 1 for 1 and for 2 were to and The of rat Oatp14 cDNA was as that of BSAT1 for in a of acid it was that this was of an by the of Oatp14 cDNA in was into the and into cells by with according to the and were by in the presence of sulfate cells were in with and sulfate at with and were for the with with was by the to the in the presence and absence of inhibitors cells had been and with and to at for the efflux study, cells were with at for and with by in the absence of with at The uptake and efflux were at by The with the cells and was determined in a The of were used to protein by the method of J. Biol. Chem. Full Text PDF PubMed Google Scholar) with as a uptake is as the concentration determined as the of with the cells by the uptake was by the uptake by vector-transfected cells from that by Oatp14-expressed cells. were from the = is the uptake of the substrate is the substrate concentration in the is the and is the uptake the the was to the uptake The were to the by analysis with as the of the and the was used for for transport were of and were purchased from Japan). had free to and at the of hyperthyroid and involved a of the of et al. J. 1997; PubMed Google Scholar). was by the of an for thyroid in the thyroid to the or was by to at the and be within 2 of the and within 1 was produced by capillary of Oatp14 expression of Oatp14 mRNA in rat was investigated by Northern blot analysis was at in the brain. were in mRNA from including the liver, and and Immunohistochemical of The expression of Oatp14 in the choroid brain homogenate, and brain capillary was by Western blot analysis protein was at in the choroid brain homogenate, and brain capillary. were when for Oatp14 was that the were specific for the the localization of Oatp14 in brain capillary endothelial cells, staining was out using for were in brain capillary endothelial cells. The were the plasma membrane of brain capillary endothelial cells. The was by the of Oatp14 with of Oatp14 the of the uptake of [14C]cerivastatin [35S]TRO-S and by Oatp14-expressed cells and vector-transfected cells. uptake by Oatp14-expressed cells is greater than that by vector-transfected cells. uptake and the The for the uptake by Oatp14 were determined by analysis and in The uptake of organic anions by Oatp14 was and the results are in The uptake of [14C]E3040 [14C]E3040 and T3 by Oatp14-expressed cells was significantly greater compared with that by vector-transfected Although the triiodothyronine uptake by Oatp14-expressed cells was significantly greater than that by vector-transfected cells, the uptake for T3 was ∼6-fold than that of T4 and reverse T3 by Oatp14 The in the uptake of [3H]TLCS, sulfate and was between Oatp14-expressed and vector-transfected cells, the of uptake were specificity of uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is uptake is in a and for in a Oatp14 can mediate bidirectional cells were preloaded with for by in the absence of The with was in Oatp14-expressed cells compared with that in vector-transfected cells, and the elimination were and 0.006 the uptake of were investigated pravastatin, ES, and acid were potent inhibitors of Oatp14, whereas was a and substrates of organic anion and had no effect the whereas was a and had no but was a and effect by and or was The of probenecid, BSP, ES, DPDPE, T3, and T4 for the uptake of by Oatp14-expressed cells are in of probenecid, BSP, ES, DPDPE, T3, and T4 the uptake of cells. The of taurocholate DPDPE T3 and T4 the uptake of by cells were at The specific uptake was by the uptake by vector-transfected cells from that by cells. and the uptake by and vector-transfected cells, respectively. the = of compounds the uptake of by cells. The of compounds the uptake of by cells were at are as a with to the determined in the absence of the = sulfate; for in a of and the of Oatp14 in the Brain of and the expression of Oatp14 in the brain capillary were investigated by and Western and and Western revealed that the expression levels of Oatp14 mRNA and protein were up- and down-regulated under and hyperthyroid conditions, respectively. the present study, we the substrate specificity of Oatp14, as well as its tissue distribution and localization in the brain. Oatp14 is expressed in the brain capillary and choroid plexus. the uptake of and reverse T3, as well as organic anions such as E217βG, and TRO-S, its in the membrane transport of these in the brain capillary. T3 and its T4, are produced in the thyroid and into the T3 plays an role in brain via to specific D. A. Neurol. Scopus Google Scholar). of thyroid and in the brain and Rev. 1997; PubMed Scopus Google Scholar, Pharmacol. Ther. 94: PubMed Scopus Google Scholar). T3 is to the brain and as T4 from which T3 is produced by type 2 iodothyronine D. A. Neurol. Scopus Google Scholar). Therefore, the brain uptake of T4 from the circulating blood is the in subsequent of thyroid in the brain. is a specific transport for T4 in brain capillary endothelial cells The brain uptake of T4 was in G.A. PubMed Scopus Google Scholar) but in mice Life Sci. PubMed Scopus Google Scholar). of the transport and of Oatp14 us of Oatp14 cDNA into cells in a in the uptake of T4, as well as reverse T3, an of T4 produced by type iodothyronine deiodinase. Although the uptake of T3 by Oatp14-expressed cells was significantly greater than that by vector-transfected cells T3 was by vector-transfected cells the uptake in vector-transfected cells is to specific transport system(s) for T3 or The transport activity for T3 by Oatp14, by of the uptake by vector-transfected cells from that by Oatp14-expressed cells, was ∼6-fold lower than that for T4 and reverse T3 by Oatp14 the of T3 and reverse T3 are The of T3 for Oatp14 was greater than that of T4 and this may in transport activity for T3 by Oatp14 can mediate bidirectional the efflux of T4 is in Oatp14-expressed cells and it is that Oatp14 is involved in the uptake and efflux of its through the brain capillary Involvement of Oatp14 in maintaining of T4 in the brain was by the in expression levels of Oatp14 in the brain capillary under hypo- and hyperthyroid The expression of Oatp14 in the brain capillary as Oatp14 was for maintaining the concentration of T4 in the central nervous up- and down-regulated under and hyperthyroid conditions, is to that in expression D. A. Neurol. Scopus Google Scholar). expression the of T4 to T3 to for the in the brain concentration of T4 and Therefore, we hypothesize that Oatp14 is involved in the uptake of T4 through the brain to Oatp14, the isoform of rat is the transporter for T3 and T4 uptake by the brain from the circulating blood in The uptake of T3 and T4 was significantly increased in with T. Kakyo M. Sakagami H. Tokui T. Nishio T. Tanemoto M. Nomura H. Hebert S.C. Matsuno S. Kondo H. Yawo H. J. Biol. Chem. 1998; 273: 22395-22401Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). Oatp2 been identified in the and membrane of brain capillary endothelial cells (15Gao B. Stieger B. Noe B. Fritschy J.M. Meier P.J. J. Histochem. Cytochem. 1999; 47: 1255-1264Crossref PubMed Scopus (269) Google Scholar). is that Oatp14 and Oatp2 and for T4 in the brain the of Oatp2 were greater than that of Oatp14 T. Kakyo M. Sakagami H. Tokui T. Nishio T. Tanemoto M. Nomura H. Hebert S.C. Matsuno S. Kondo H. Yawo H. J. Biol. Chem. 1998; 273: 22395-22401Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). uptake from the circulating blood into endothelial cells, T4 to the membrane to the brain and brain cells. this is carrier-mediated of transport been in L. Meier P.J. N. Pharmacol. 2000; PubMed Scopus Google Scholar). Oatp14 and Oatp2 are transporters involved in the of thyroid are to the localization of Oatp14 in the brain capillary and to its to the brain uptake of T4 into the brain. Pardridge et al. W.M. PubMed Scopus Google Scholar) that the brain uptake of T3 was and inhibited by T4 using technique of and Oatp2 may for the brain uptake of T3 in the brain capillary. Oatp14 was in the choroid by Western blot analysis The choroid is in the and and the between the and the circulating blood as a barrier to the central nervous in with the BBB J. 1997; PubMed Scopus Google Scholar, 2000; 20: PubMed Scopus Google Scholar). The brain distribution of T3 and T4 is to cells and and, transport via the choroid for the brain distribution the Brain Res. 1991; PubMed Scopus Google Scholar). speculated in the of brain capillary endothelial cells, it is that Oatp14 as an uptake system to T4 to cells and in the choroid plexus. to Oatp14 of amphipathic organic such as E217βG, and TRO-S, as substrates their transport activity was lower than that of T4, and Because Oatp14 can mediate the bidirectional it is that Oatp14 is involved in the efflux of organic anions such as E217βG from the brain when it is microinjected into the cerebral and in the efflux of T4 and reverse T3 from the brain. The spectrum of inhibitors of Oatp14 was with the transporter in vivo (18Sugiyama D. Kusuhara H. Shitara Y. Abe T. Meier P.J. Sekine T. Endou H. Suzuki H. Sugiyama Y. J. Pharmacol. Exp. Ther. 2001; 298: 316-322PubMed Google Scholar), but be to this the results using cDNA from rodents can be to the human is an important an isoform in which Oatp14 in acid a substrate specificity to Oatp14 F. Hagenbuch B. Stieger B. U. G. Meier P.J. 16: PubMed Scopus Google Scholar). Northern blot analysis expression of in the brain and and, to a but the localization in the brain of substrate specificity and is to be the human of Oatp14, and it may be suggested that is involved in the uptake of T4 from the circulating blood into the central nervous system the brain capillary and choroid plexus. of the of T4 to the brain it is that of the gene may be with a thyroid characterized by to thyroid we have characterized Oatp14 in of its substrate specificity and localization in the brain and that Oatp14 T4, as well as organic including glucuronide and sulfate Oatp14 is the plasma membrane of brain capillary endothelial cells and involved in the uptake of T4 from the blood to the central nervous Oatp14 is of the for maintaining of T4 and, ultimately, T3 in the brain.