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Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan
Address all correspondence and requests for reprints to: Yuichi Sugiyama, Ph.D., Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp.
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Introduction |
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The thyroid hormones are produced by the thyroid gland. L-T4, the prehormone, is the major form in the circulating blood and is converted to the active form, T3, by the iodothyronine-deiodinase in peripheral organs. T3 exerts its action through the nuclear receptors and regulates the expression of genes, such as nerve growth factor, tropomyosin-related kinase A (trkA), and common neutrotrophin receptor p75 (p75NTR), in the brain (3). It has been proposed that serum-free T4 and T3 concentrations correlate with the activity level of thyroid hormone-dependent processes (free hormone hypothesis) (4). To exert their effect in the central nervous system, free thyroid hormones in the circulating blood have to cross the barriers of central nervous systems, the blood-brain (BBB) and the blood-cerebrospinal fluid barriers formed by the brain capillary endothelial cells and choroid plexus epithelial cells, respectively. Dratman and colleagues (5, 6) investigated the contribution of the transport via these pathways to thyroid hormone delivery to the central nervous system using autoradiography. The distribution of radioactivity associated with T4, T3, and rT3 was limited to the circumventricular organs after intracerebroventricular administration, and so the transport across the BBB is considered to be a major pathway for the delivery of thyroid hormones in the circulating blood to regions of the brain (5, 6).
BBB is formed by brain capillary endothelial cells, which are characterized by highly developed tight junctions and a paucity of fenestra and pinocytotic vesicles. Due to these characteristics, they act as a physical barrier to separate the brain extracellular fluid from the circulating blood. Pardridge (7) demonstrated saturable uptake of T3 by the brain using the intracarotid injection method (Brain Uptake Index method) and suggested that there is a specific transport mechanism for T3 at the BBB. However, the transport mechanism for T4 across the BBB remains controversial. The uptake of T4 by the brain has been reported to be saturable in dogs (8) but nonsaturable in mice (9). The reason for this discrepancy remains unknown.
Recently organic anion transporting polypeptide 14 (Oatp14; Slc21a14) has been cloned from the rat brain cDNA library using gene microarray techniques by comparing the gene-expression profile of cDNA from the brain capillary with that from the liver and kidney (10). Oatp14 was highly enriched in the brain capillary, compared with brain homogenate, liver, and kidney (10, 11). Functional expression of OATP-F, the human ortholog of Oatp14, revealed that T4 and the inactive metabolite, rT3, are high-affinity substrates (12), and rOatp14 accepts amphipathic organic anions, such as cerivastatin, 17ß-estradiol-D-17ß-glucuronide (E217ßG), and troglitazone sulfate as substrates in addition to T4 and rT3 (11). The transport activity of T3 by OATP-F and rOatp14 was small, compared with that of T4 and rT3. Because the expression level of rOatp14 is controlled by the plasma thyroid hormone concentrations (11), it has been hypothesized that rOatp14 is involved in the uptake of thyroid hormones by the brain. There are additional candidate transporters for the transport of thyroid hormones at the brain: Oatp2, another isoform of the Oatp family, large neutral amino acid transporters, and monocarboxylate transporter 8 (MCT8) (13, 14, 15, 16, 17). The present study is aimed at investigating whether mOatp14 is involved in the brain uptake of T4 across the BBB. Stable transformants of mOatp14 were established to reveal the spectrum of inhibitors. The in situ brain perfusion technique was carried out to investigate the uptake of T4 across the BBB, and the effect of inhibitors for mOatp14, Oatp2, and neutral amino acid transporter was examined to reveal the contribution of mOatp14.
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Materials and Methods |
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Animals
Adult male ddY mice (28–35 g, 7–8 wk old) were obtained from Japan SLC, Inc (Shizuoka, Japan). All the animals used throughout this study had free access to food and water. The animal experiments were approved by the Institution Animal Care Committee (Graduate School of Pharmaceutical Science, The University of Tokyo), and performed according to its guidelines.
Cloning of mouse Oatp14 (mOatp14) cDNA and construction of a stable transfectant
Based on the nucleotide sequence reported by Okazaki et al. (GenBank accession no. NM_021471), the cDNA encoding a full open reading frame of mOatp14 was cloned from mouse brain cDNA using PCR. The mOatp14 cDNA was subcloned into pcDNA3.1(+) (Invitrogen, Carlsbad, CA) and transfected into HEK293 cells by lipofection with FuGENE6 (Roche Diagnostics, Basel, Switzerland) according to the manufacturer’s protocol. The transfectants were selected by culturing them in the presence of G418 sulfate (800 µg/ml) (Gibco BRL, Gaithersburg, MD). The transfectants were maintained in DMEM (Gibco) supplemented with 10% fetal bovine serum, 1% antibiotic-antimycotic (Gibco), and G418 sulfate (400 µg/ml) at 37 C with 5% CO2 and 95% humidity.
Transport study
Uptake was initiated by adding the radiolabeled ligands to the incubating buffer in the presence and absence of inhibitors after cells had been washed twice and preincubated with Krebs-Henseleit buffer at 37 C for 15 min. The Krebs-Hensleit buffer consisted of 23.8 NaHCO3, 118 NaCl, 4.83 KCl, 1.2 MgSO4, 0.96 KH2PO4, 1.53 CaCl2 5 D-glucose, and 12.5 HEPES (millimoles) adjusted to pH 7.4. The uptake was terminated at designated times by adding ice-cold buffer, and cells were washed three times. The radioactivity associated with cell and medium specimens was determined in a liquid scintillation counter and 
-counter. Ligand uptake is given as the cell-to-medium concentration ratio determined as the amount of ligand associated with the cells divided by the medium concentration. Specific uptake was obtained by subtracting the uptake of vector-transfected cells from that by mOatp14-HEK.
In situ brain perfusion
In situ brain perfusion was carried out according the previous report by Dagenais et al. (19). Briefly, mice were anesthetized by ip injection of pentobarbital sodium (50 mg/kg), and the right common carotid artery was catheterized with polyethylene tubing (0.2 mm inner diameter x 0.5 mm outer diameter) mounted on a 30-gauge needle. Before insertion of the catheter, the common carotid artery was ligated caudally. During surgery, body temperature was maintained with a heated plate. The syringe containing the perfusion fluid was placed in an infusion pump (Packard Instruments, Meriden, CT) and connected to the catheter. Before perfusion, the thorax of the animal was opened, the heart was cut, and perfusion was started immediately at a flow rate of 1.0 ml/min. The perfusion fluid consisted of Krebs-Henseleit bicarbonate buffer (millimoles): 25 NaHCO3, 118 NaCl, 4.7 KCl, 1.2 MgSO4·7H2O, 1.2 NaH2PO4·2H2O, 1.2 CaCl2·2H2O, and 10 D-glucose. The perfusion was gassed with 95% O2 and 5% CO2 for pH control (7.4) and warmed to 37 C in a water bath. The perfusate contained a vascular space marker ([14C]sucrose) of 2 µCi/ml and perfusion was terminated by decapitation of a number of the animals at selected times. The brain was removed, and the cortex of the right cerebral hemisphere was placed in a tared vial and weighed. The radioactivity associated with the brain and perfusion fluid specimens was determined in a liquid scintillation counter.
Brain vascular volume was estimated from the tissue distribution of [14C] sucrose, which is known to diffuse very slowly across the BBB, using the following equation:
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The initial uptake clearance was calculated from the following equation:
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Kinetic analysis
Kinetic parameters were obtained from the following (Michaelis-Menten) equation:
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Inhibition constants (Ki) for mOatp14-mediated transport were calculated from the following equation assuming competitive inhibition:
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Capillary isolation
The method of capillary isolation was described by Ball et al. (21) and Dallaire et al. (22). Capillary isolation was performed by using the modified method. Briefly, the cortex was homogenized in 0.32 M sucrose (ratio 1 g brain/20 ml sucrose) using a Polytron homogenizer. The homogenate was centrifuged at 4 C at 2200 x g for 10 min, and the resulting pellet was suspended in 25% BSA and centrifuged at 4 C at 2200 x g for 10 min. The supernatant was decanted, and the pellet was washed three times with buffer: 10 mM Tris-Cl, 0.5 mM dithiothreitol (pH 7.6). The purity of the brain capillary enrichment fraction was examined by estimating the -GTP activity.
Northern blot analysis
A commercially available hybridization blot containing poly A+ RNA from various mouse tissues (mouse MTN blot, CLONTECH, Palo Alto, CA) was used for the Northern blot analysis. A fragment (position numbers 86–841) from mOatp14-ORF was used as a probe. The master blot filter was hybridized in Perfecthyb Plus (Sigma, St. Louis, MO) with the 32P-labeled probe at 68 C according to the manufacturer’s instructions. Finally, the filter was washed under high stringency conditions (0.1x saline sodium citrate: 0.15 M NaCl and 0.015 M sodium citrate) and 0.1% sodium dodecyl sulfate at 65 C.
Western blot analysis
Antiserum against the carboxyl-terminal of rat Oatp14 (rOatp14) (11) was available for mOatp14. The specimens were loaded onto a 10% SDS-PAGE with a 3.75% stacking gel. Proteins were electroblotted onto a polyvinylidene difluoride membrane (Pall, Port Washington, NY). The membrane was blocked with Tris-buffer saline containing 0.05% Tween 20 and 3% skimmed milk for 1 h at room temperature. After incubation with the primary antibody, detection was carried out by binding a horseradish peroxidase-labeled antirabbit IgG antibody (Amersham Bioscience, Buckinghamshire, UK). Regional difference of mOatp14 was examined using mouse multiple brain tissue region-specific blots (Geno Technology, St. Louis, MO).
Immunohistochemical staining
Adult mice were perfused with 4% paraformaldehyde/PBS. The cerebrum was isolated and stored in 4% paraformaldehyde/PBS for 2 h at 4 C. Before sectioning, the cerebrum was immersed in 20% sucrose at 4 C. Cryostat sections (10 µm thick) were fixed in methanol at –20 C for 10 min, washed with PBS, and blocked with 1% BSA/PBS at room temperature for 4 h, and then primary antibodies (rabbit anti-rOatp14 serum (1:100 dilution in 1% BSA/PBS) and C219 (1:40 dilution in 1% BSA/PBS) were kept at 4 C for 44 h. For detection of the signals, sections were incubated with secondary antibodies (Alexa Fluor 568 antirabbit IgG and Alexa Fluor 488 antimouse IgG, diluted to 1:200; Molecular Probes, Eugene, OR) for 1 h, and the nucleic acid was simultaneously stained with TO-PRO-3 iodide (Molecular Probes) and mounted in Vectashield mounting medium (Vector Laboratories, Burlingame, CA).
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, A–E, shows the time profiles of the uptake of [125I]L-T4, [125I]rT3, [3H]E217ßG, [125I]T3, and [3H]E-sul by mOatp14-expressed HEK293 cells and vector-control cells. Specific uptake of [125I]L-T4, [125I]rT3, and [3H]E217ßG by mOatp14-HEK was observed, whereas the uptake of [125I]T3 and [3H]E-sul by mOatp14-HEK was slightly greater than that by vector transfected cells. The mOatp14-mediated E217ßG uptake increased linearly over 2 min, whereas that of T4 and rT3 increased linearly over 5 min. The mOatp14-mediated uptake followed Michaelis-Menten kinetics (Fig. 1, F–H). The kinetic parameters for the uptake by mOatp14 were determined by nonlinear regression analysis and are summarized in Table 1.
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), whereas 3,5-T2, digoxin, benzylpenicillin, and leucine (Leu) had no inhibitory effect on mOatp14-mediated transport (data not shown). The respective Ki values are summarized in Table 2.
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). The distribution of mOatp14 in the brain was examined by Western blot analysis. There were two bands nearly the expected size. The band with the greater molecular mass was detected almost ubiquitously but not in the cerebellum (Fig. 3C). Because the mRNA of mOatp14 was not detected in the cerebellum by RT-PCR (data not shown), the band detected at the lower molecular weight in the cerebellum is unlikely to be associated with mOatp14. The expression of mOatp14 in the choroid plexus-, brain homogenate-, and brain capillary-enriched fraction was examined by Western blot analysis. The enrichment factor of GTP of the isolated brain capillary-enriched fraction was 10.7. Immunoreactive protein was detected at approximately 90,000 in the choroid plexus-, brain homogenate-, and the isolated brain capillary-enriched fraction. The signal of the brain capillary band was stronger than that of the brain homogenate (Fig. 3B).
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In situ brain perfusion
The time profile of the uptake of [125I]L-T4 by the brain (cortex and cerebellum) is shown in Fig. 4A. The uptake clearance by the cerebral cortex was 3-fold greater than that by the cerebellum (583 ± 71 vs. 185 ± 27 µl/min·g tissue) (Fig. 4B). The distribution volume of sucrose was 11.8 ± 0.5 and 19.2 ± 1.5 µl/g tissue for the cerebral cortex and cerebellum, respectively. The following experiments were performed for the brain uptake determined at 60 sec. The uptake by the cerebral cortex was saturable in mice (Fig. 5). The Km, Vmax, and clearance corresponding to the nonsaturable components of [125I]T4 uptake by the cerebral cortex were 1.02 ± 0.16 µM, 423 ± 65 pmol/min·mg protein, and 15.6 ± 7.8 µl/min·g tissue, respectively. However, the fraction of saturation was smaller for the uptake of T4 by the cerebellum (140 ± 30 vs. 44.8 ± 4.6 µl/min·g tissue at 0.01 and 10 µM, respectively). The uptake of [125I]L-T4 by the cerebral cortex was inhibited markedly by taurocholate and partly by E-sul, whereas Leu, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), benzylpenicillin, and digoxin had no effect. E217ßG had a weak inhibitory effect (Fig. 6).
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Discussion |
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). Furthermore, the substrate recognition by mOatp14 was investigated by a cis-inhibition study using thyroid hormones and related agents (Fig. 2, E–H). Because the Ki value of D-T4 (stereoisomer of L-T4) was similar to the Km value of L-T4, there is no stereosensitivity in the substrate recognition by mOatp14 (Table 2). rT3 potently inhibited T4 uptake, whereas T3 had a 25-fold greater Ki value than T4 and rT3, and 3,5-T2 had no effect (Table 2). These results suggest the importance of iodine attached to the outer ring for high-affinity recognition of T4 and rT3 by mOatp14.
Probenecid, taurocholate, E-sul, and E217ßG were moderate or weak inhibitors of mOatp14 (Table 2). Digoxin and benzylpenicillin, which are good substrates of Oatp2 and Oat3, respectively, had no effect on the uptake of T4 by mOatp14, and neutral amino acids (Leu, phenylalanine, tryptophan, and tyrosine) had no effect either (data not shown). The contribution of mOatp14 and other transporters can be evaluated using these compounds as inhibitors. The Ki values of these compounds for mOatp14 were 10-fold greater than the previously reported values determined for the uptake of E217ßG by rOatp14 (11). There was a discrepancy of more or less 1 order of magnitude in the Ki values of inhibitors for rat and mouse Oatp14, even though they were determined by the same methods, whereas the Km values of T4 and E217ßG for mOatp14 were comparable with those for rOatp14. Different test substrates were used to determine the Ki values of inhibitors (E217ßG for rOatp14 vs. T4 for mOatp14). Because E217ßG had a lower inhibitory effect on T4 uptake by mOatp14 than expected from its Km value, the Ki value of E217ßG will be greater than its own Km value. As far as two substrate compounds share the same substrate recognition sites in the transporter, the Ki value of one compound for the uptake of the other should be the same as its own Km value. The discrepancies in the kinetic parameters for different substrates (E217ßG and T4) suggest that Oatp14 has at least two different substrate recognition sites. Therefore, the difference in the Ki value for the uptake of E217ßG and T4 by rat and mouse is not ascribed to the species difference but presumably accounted for by multiple recognition sites for T4 and E217ßG by mOatp14 as reported in rOatp2 (23). The Ki value of E217ßG for the digoxin uptake by rOatp2 (0.04 µM) was much smaller than its Km value (1 µM) (23).
mOatp14 is widely expressed throughout the brain, and strong expression was observed in the posterior cortex, olfactory bulb, thalamus, midbrain and pons, whereas the expression in the cerebellum was below detection. Regional differences have also been observed in human OATP-F, which is not expressed in the cerebellum or pons (12). Li et al. (10) and Sugiyama et al. (11) demonstrated that rOatp14 is highly enriched in the isolated brain capillaries, and furthermore, Sugiyama et al. demonstrated that rOatp14 is expressed at plasma membrane of the brain capillaries in rats by immunohistochemical staining (11).
To investigate an involvement of mOatp14 in the T4 uptake across the BBB, the brain uptake of T4 was characterized using the in situ brain perfusion technique. The uptake of T4 was 3-fold greater in the cerebral cortex than in the cerebellum (Fig. 4B). A saturable component accounted for about 95% of the total uptake of T4 by the cerebral cortex, suggesting the important role of transporters in T4 uptake at the BBB (Fig. 5). The Km value of T4 uptake at the cerebral cortex was almost comparable with the Km value of mOatp14 (1.02 vs. 0.34 µM). T4 is highly bound to plasma T4 binding proteins (24). Based on the free hormone hypothesis, in which free T4 and T3 concentrations correlate with the activity level of thyroid hormone-dependent processes (4), free T4 will be taken up by the brain via the specific transport systems at the BBB. For mice, the range of normal serum-free T4 is approximate 10–20 pM (25), much lower than its Km value (1.02 µM), suggesting that the transport mechanism of T4 uptake across the BBB is not saturated under physiological conditions. In contrast, in the cerebellum, the fraction of saturation was small. These results are in good agreement with regional differences in the expression of mOatp14. Taurocholate completely inhibited the uptake of T4 by the cerebral cortex, and E-sul and E217ßG had a weak inhibitory effect. Partial inhibition by E-sul, even at a concentration sufficient to inhibit Oatp14-mediated transport completely, suggests that T4 uptake across the BBB cannot be fully accounted for by mOatp14, and another transporter is involved in the uptake of T4 by the cerebral cortex. The Eadie-Hofstee plot indicated that the uptake of T4 by the brain consists of a single saturable component, suggesting that the unknown transporter has a Km value similar to T4 with mOatp14. Because digoxin, benzylpenicillin, Leu, and BCH had no effect for the uptake of T4 by the cerebral cortex, the involvement of Oatp2, Oat3, and large neutral amino acid transporters can be excluded. However, several transporters are identified as thyroid hormone transporters up to now (26, 27), and this time we could not estimate the contribution of some transporters. Further studies are necessary to identify the taurocholate-inhibitable transporter involved in the uptake of T4 together with mOatp14.
In addition to the brain capillaries, Western blot analysis detected mOatp14 protein in the choroid plexus in which it is located on the basolateral membrane (Fig. 3, B and D). Previously, in situ choroid plexus perfusion experiments in sheep revealed that a saturable mechanism is responsible for the uptake of T4 through the choroid plexus from blood side to the cerebrospinal fluid (28). Apparent Km value with respect to the concentration in the injectate was 11 µM. However, taking into consideration the dilution factor after the injection, the corrected Km value was to be 1.6 µM, comparable with that determined in this study for the uptake by the cerebral cortex across the BBB. mOatp14 may play a role in the uptake of T4 at the basolateral side of the choroid plexus epithelial cells.
The present study highlights the importance of membrane transporters, especially Oatp14, for the brain uptake of T4 across the BBB. In addition to the BBB and blood-cerebrospinal fluid barrier, transporters will play an important role in the disposition of thyroid hormones in the central nervous system. Carrier-mediated uptake of T4 and T3 has been reported in primary cultured neuronal cells (29). Although the transporter uptake by brain parenchymal cells has not been identified, there are some likely candidate transporters. OATP-E, another Oatp/OATP isoform, is known to accept thyroid hormones as substrates (30) and is expressed in the brain (30). In addition to Oatp/OATP isoforms, MCT8 has been identified as a thyroid hormone transporter (17). MCT8 is expressed weakly in the brain but most abundantly in the liver (17). Recently Dumitrescu et al. (31) reported that mutations in the MCT8 gene are associated with thyroid hormonal and neurological abnormalities in humans, although whether these are due to the functional loss of MCT8 in the central nervous system remains to be elucidated. Further studies are necessary to determine the roles of transporters in regulating the disposition of thyroid hormones in the central nervous system.
Thyroid hormones are activated/inactivated by deiodinases in the brain. Of three subtypes, types 2 and 3 deiodinases are expressed in the brain. Type 2 deiodinase is responsible for the conversion T4 to T3, whereas type 3 deiodinase inactivates thyroid hormone by converting T4 to rT3, and T3 to T2 (32, 33). In the brain, type 2 deiodinase has been shown to be predominantly expressed in the nonneuronal cells and glial cells, such as tanycytes and astrocytes (32), whereas type 3 deiodinase is expressed in the neurons (33). Therefore, it can be hypothesized that T4 is transported into the brain via the BBB by specific transport systems followed by activation to T3 mainly in nonneuronal and glial cells. Thereafter, T3, produced by nonneuronal and glial cells, is taken up by neuronal cells to exert its action via the nuclear receptors followed by inactivation by type 3 deiodinase. Membrane transport processes in nonneuronal and glial cells and neurons will play an important role in regulating the effect of thyroid hormones in the central nervous system together with deiodinases.
In conclusion, taurocholate-sensitive transporters play a predominant role in the uptake of T4 across the BBB. It is suggested that mOatp14 accounts for E-sul inhibitable fraction, at least partly, and the E-sul-insensitive fraction is accounted for by unknown transporters. In addition to the BBB, Oatp14 may also play a role in the uptake of T4 in the choroid plexus.
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Footnotes |
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Abbreviations: BBB, Blood-brain barrier; BCH, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; dpm, decay per minute; E217ßG, 17ß-estradiol-D-17ß-glucuronide; E-sul, estrone-3-sulfate; Ki, inhibition constant; Km, Michaelis-Menten constant; Leu, leucine; MCT8, monocarboxylate transporter 8; mOatp14, mouse Oatp14; Oatp14, organic anion transporting polypeptide 14; rOatp14, rat Oatp14; Vbrain, volume of brain distribution; Vmax, maximum uptake rate.
Received January 19, 2004.
Accepted for publication May 19, 2004.
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