Clarification of xenobiotic recognition mechanism at the blood-placentabarrier by transporter array
Project/Area Number |
18590154
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Medical pharmacy
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Research Institution | Kyoritsu University of Pharmacy |
Principal Investigator |
SAI Yoshimichi Kyoritsu University of Pharmacy, Department of Phairmaceutics, Associate Professor (40262589)
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Co-Investigator(Kenkyū-buntansha) |
NAKASHIMA Emi Kyoritsu University of Pharmacy, Department of Pharmaceutics, Professor (90115254)
KOSE Noriko Kyoritsu University of Pharmacy, Department of Pharmaceutics, Research Fellow (60348612)
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Project Period (FY) |
2006 – 2007
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Project Status |
Completed (Fiscal Year 2007)
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Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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Keywords | Placenta barrier / Nucleoside / Nucleobase / Transporter / Drug Drug Interaction / Contribution / Anti-virus drug / recognition of xenobiotics / トロホブラスト / 妊娠時薬物療法 / 有機アニオン / 定量PCR / Caco-2細胞 / エストロン |
Research Abstract |
The uptake mechanisms of nucleosides at the blood-placenta barrier were clarified by using the rat syncytiotrophoblast cell line TR-TBT 18d-1. The initial uptake of [3H]uridine and [3H]adenosine by TR-TBT 18d-1 were sodium-independent and were sensitive to nitrobenzylthioinosine. The Km value of adenosine uptake was approximately 17 μM. These results suggested involvement of equilibrative nucleoside transporters ENT1 and ENT2. The uptakes were significantly reduced by several nucleoside drugs, including zidovudine (AZT), cytarabine, vidarabine, mizoribine and caffeine. The effects were small within the therapeutic concentration ranges. Therefore, these drugs at the therapeutic concentrations might have little influence on maternal-to-fetal nucleoside transfer. The uptake mechanism of AZT was characterized. Initial uptake of AZT was sodium-independent and saturable (Km, approx. 16 μM). Thymidine and 2' -deoxyuridine strongly inhibited the uptake, but nitrobenzylthioinosine, probenecid a
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nd cimetidine had little effect on the uptake. Cyclosporin A, Ko143 and probenecid had little effect on the steady state AZT accumulation, suggesting that transporter-mediated efflux of AZT is not substantial. These results indicate that the saturable AZT uptake by TR-TBT 18d-1 was mediated by a so-far unidentified transporter. A human enterocyte model Caco-2 cell exhibits estrone-3-sulfate uptake, but the responsible transporters have not been clarified, yet. We have examined the contribution of OATP2B1 to the uptake in comparison with that of its homolog genes. The OATP2B1 mRNA expression was higher than that of OATP3A1 or OATP4A1 in Caco-2 and in human jejunum biopsies. The estrone-3-sulfate uptakes normalized to OATP2B1 mRNA expression were similar in Caco-2 cells and HEK293/OATP2B1 cells. The specific activity of OATP2B1 per mRNA expression was much higher than that of OATP3A1 and OATP4A1. These results suggest that OATP2B1 is predominantly responsible for the uptake in Caco-2 cells. This method can be applied to determine the contribution of each transporter in the placenta barrier. Less
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Report
(3 results)
Research Products
(106 results)
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[Journal Article] Characterization of the mechanism of zidovudine uptake by rat conditionally immortalized syncytiotrophoblast cell line TR-TBT2008
Author(s)
Sai Y, Nishimura T, Shimpo S, Chishu T, Sato K, Kose N, TerasakiT, Mukai C, Kitagaki S, Miyakoshi N, Kang YS, Nakashima E.
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Journal Title
Description
「研究成果報告書概要(和文)」より
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Peer Reviewed
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[Journal Article] Characterization of the mechanism of zidovudine uptake by rat conditionally immortalized syncytiotrophoblast cell line TR-TBT2008
Author(s)
Sai, Y, Nishimura, T, Shimpo, S, Chishu, T, Sato, K, Kose, N, Terasaki, T, Mukai, C, Kitagaki, S, Miyakoshi, N, Kang, YS, Nakashima, E
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[Journal Article] Potential of various drugs to inhibit nucleoside uptake in rat syncytiotrophoblast cell line, TR-TBT 18d-12008
Author(s)
Chishu, T, Sai, Y, Nishimura, T, Sato, K, Kose, N, Nakashima, E
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Journal Title
Placenta 29
Pages: 461-467
Description
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[Journal Article] Involvement of multidrug resistance-associated protein 2 (Abcc2) in molecular weight-dependent biliary excretion of {beta}-lactam antibiotics2008
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Kato, Y, Takahara, S, Kato, S, Kubo, Y, Sai, Y, Tamai, I, Yabuuchi, H, Tsuji, A
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Journal Title
Drug Metab Dispos 36
Pages: 1088-1096
Description
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[Journal Article] Characterization of the mechanism of zidovudine uptake by ratconditionanylly immortalized syncytiotrophoblast cell line TR-TBT.2008
Author(s)
Sai Y, Nishimura T, Shimpo S, Chishu T, Sato K, Kose N, TerasakiT, Mukai C, Kitagaki S, Miyakoshi N, Kang YS, Nakashima E.
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[Journal Article] Transport of carnitine and acetylcarnitine by carnitine/organic cation transporter (OCTN) 2 and OCTN3 into epididymal spermatozoa2007
Author(s)
Kobayashi, D, Tamai, I, Sai, Y, Yoshida, K, Wakayama, T, Kido, Y, Nezu, J, Iseki, S, Tsuji, A
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Reproduction 134
Pages: 651-658
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[Journal Article] Heterophilic binding of the adhesion molecules poliovirus receptor and immunoglobulin superfamily 4A in the interaction between mouse spermatogenic and Sertoli cells2007
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Wakayama, T, Sai, Y, Ito, A, Kato, Y, Murakami, Y, Nakashima, E, Tsuji, A, Kitamura, Y, Iseki, S
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Journal Title
Biol Reprod 76
Pages: 1081-1090
NAID
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[Journal Article] Altered expression of basement membrane-related molecules in rat brain pericyte, endothelial, and astrocyte cell lines after transforming growth factor-β1 treatment2007
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Kose, N, Asashima, T, Muta, M, Iizasa, H, Sai, Y, Terasaki, T, Nakashima, E
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Drug Metab Pharmacokinet 22
Pages: 255-266
NAID
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[Journal Article] c-Met expression in pericytes : implicationsfor atherosclerotic plaque Heagerty A, Canfield A, Alexander M., Hepatocyte growth factor and development2007
Author(s)
Liu, Y, Wilkinson, F, Kirton, J, Jeziorska, M, Iizasa, H, Sai, Y, Nakashima, E
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Journal Title
J Pathol 212
Pages: 12-19
Description
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[Journal Article] Characterization of the uptake mechanism for a novel loop diuretic, M17055, in Caco-2 cells : involvement of organic anion transporting polypeptide (OATP)-B2007
Author(s)
Nishimura, T, Kubo, Y, Kato, Y, Sai, Y, Ogihara, T, Tsuji, A
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Journal Title
Pharm Res 24
Pages: 90-99
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[Journal Article] Organic cation/carnitine transporter octn2 (slc22a5) is responsible for carnitine transport across apical membranes of small intestinal epithelial cells in mouse2007
Author(s)
Kato, Y, Sugiura, M, Sugiura, T, Wakayama, T, Kubo, Y, Kobayashi, D, Sai, Y, Tamai, I, Iseki, S, Tsuji, A
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Journal Title
Mol Pharmacol 70
Pages: 829-837
Description
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[Journal Article] Involvement of organic anion transporting polypeptide OATP-B(OATP2B1) in apical uptake of estrone-3-sulfate by human intestinal Caco-2 cells2006
Author(s)
Sai, Y, Kaneko, Y, Ito, S, Kato, Y, Tamai, I, Artursson, P, Tsuji, A
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Journal Title
Drug Metab Dispos 34
Pages: 1423-1431
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[Presentation] The expression levels of ERM during pregnancy and role of ezrin in localization of GLUT1 and P-glycoprotem in placenta2007
Author(s)
Higuchi K, Wada M, Deguchi M, Horieya S, Kose N, Nishimura T, Sai Y, Wakayama T, Tamura A, Tsukita S, Nakashima E.
Organizer
2007 AAPS Annual Meeting and Exposition
Place of Presentation
San Diego,CA,USA
Year and Date
2007-11-15
Description
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[Presentation] Characterization of the placental transport mechanism of erythromycin using syncytiotrophoblast cell line TR-TBT 18d-12007
Author(s)
Nishimura, T, Sai, Y, Ochi, K, Kose, N, Nakashima, E
Organizer
2007 AAPS Annual Meeting and Exposition
Place of Presentation
San Diego, CA, USA
Year and Date
2007-11-15
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[Presentation] The expression levels of ERM during pregnancy and role of ezrin in localization of GLUT1 and P-glycoprotein in placenta2007
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Higuchi, K, Wada, M, Deguchi, M, Horieya, S, Kose, N, Nishimura, T, Sai, Y, Wakayama, T, Tamura, A, Tsukita, S, Nakashima, E
Organizer
2007 AAPS Annual Meeting and Exposition
Place of Presentation
San Diego, CA, USA
Year and Date
2007-11-15
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[Presentation] The expression levels of ERM during pregnancy and role of ezrin in localization of GLUT1 and P-glycoprotein in placenta.2007
Author(s)
Higuchi K, Wada M, Deguchi M, Horieya S, Kose N, Nishimura T, Sai Y, Wakayama T, Tamura A, Tsukita S, Nakashima E..
Organizer
2007AAPS Annual Meeting and Exposition
Place of Presentation
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Year and Date
2007-11-15
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[Presentation] Involvement of nucleoside transporters in the uptake of anti-HIV drugs, 2', 3'-dideoxyinosine and 3'-azido- 3'-deoxythimidine by a conditionally immortalized syncytiotrophoblast cell line, TR-TBT2007
Author(s)
Nisimura, T, Sato, K, Sai, Y, Kose, N, Shimpo, S, Nakashima, E
Organizer
8th International ISSX Meeting
Place of Presentation
Sendai, Japan
Year and Date
2007-10-12
Description
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[Presentation] Quantitative analysis of mRNA expression level of ABC transporters in rat primary cultured syncytiotrophoblasts and conditionally immortalized syncytiotrophoblast cell line, TR-TBTs2007
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Sai, Y, Maeda, T, Koizumi, T, Kose, N, Nishimura, T, Nakashima, E
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8th International ISSX Meeting
Place of Presentation
Sendai, Japan
Year and Date
2007-10-12
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[Presentation] Alteration of expression level of ezrin during pregnancy and influence to the localization of GLUT1 and P-gp in the placenta2007
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Higuchi K, Wada M, Deguchi M, Horieya S, Rose N, Nishimura T, Sai Y, Wakayama T, Tamura A, Tsukita S, Nakaclhima E.
Organizer
日本薬物動態学会ビジョン・シンポジウム
Place of Presentation
東京
Year and Date
2007-07-19
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[Presentation] Functional characterization of nucleoside analogues uptake at the placenta and its relevance to drug interaction2007
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Sato, K, Chisyu, T, Sai, Y, Nishimura, T, Kose, N, Nakashima, E
Organizer
JSSX Vision Symposium 2007
Place of Presentation
Tokyo
Year and Date
2007-07-19
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[Presentation] 「研究成果報告書概要(欧文)」より2007
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Higuchi, K, Wada, M, Deguchi, M, Horieya, S, Kose, N, Nishimura, T, Sai, Y, Wakayama, T, Tamura, A, Tsukita, S, Nakashima, E
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JSSX Vision Symposium 2007
Place of Presentation
Tokyo
Year and Date
2007-07-19
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[Presentation] Alteration of expression level of ezrin duridng pregnancy and influence to the locahzation of GLUT1 and P-gp in the placenta.2007
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Higuchi K, Wada M, Deguchi M, Horieya S, Kose N, Nishimura T, Sai Y, Wakayama T, Tamura A, Tsukita S, Nakashima E..
Organizer
日本薬物動態学会ビジョン・シンポジウム
Place of Presentation
東京
Year and Date
2007-07-19
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[Presentation] Transport mechanism and drug sensitivity of uridine, adenosine and hypoxanthine influx from apical membrane of rat syncytiotrophoblast cell line, TR-TBT 18d-12007
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Chishu, T, Sai, Y, Kose, N, Sato, K, Nishimura, T, Nakashima, E
Organizer
4th World Conference on Drug Absorption, Transport and Delivery
Place of Presentation
Kanazawa, Japan
Year and Date
2007-06-21
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[Presentation] Uptake mechanisms of anti-HIV drugs, 2', 3'-dideoxyinosine and 3'-azido- 3'-deoxythimidine by a conditionally immortalized syncytiotrophoblast cell line, TR-TBT2007
Author(s)
Sato, K, Sai, Y, Kose, N, Shimpo, S, Nakashima, E
Organizer
Pharmaceutical Sciences World Congress 2007
Place of Presentation
Amsterdam, Netherlands
Year and Date
2007-04-25
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[Presentation] Placental transport of erythromycin evaluated using syncytiotrophoblast cell line TR-TBT 18d-12007
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Sai, Y, Ochi, K, Kose, N, Nishimura, T, Nakashima, E
Organizer
4th World Conference on Drug Absorption, Transport and Delivery
Place of Presentation
Kanazawa, Japan
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[Presentation] 12007
Author(s)
Sai Y, Ochi K, Kose N, Nishiimura T, Nakashima E..
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4th World Conference on Drug Absorption, Transport and Dglivery
Place of Presentation
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[Presentation] Functional characterization of nucleobase uptake at the placenta and its relevance to the fetoplacental toxicity2006
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Sai, Y, Chishu, T, Koase, M, Sato, K, Shimpo, S, Kose, N, Nakashima, E
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21st Annual JSSX Meeting
Place of Presentation
Tokyo
Year and Date
2006-11-29
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[Presentation] The functions of transporters and RNA editing2006
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Asano, K, Kose, N, Sai, Y, Iizasa, H, Nakashima, E
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2006 AAPS Annual Meeting and Exposition
Place of Presentation
San Antonio, TX, USA
Year and Date
2006-11-02
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[Presentation] Apical localization of ezrin in syncytiotrophoblast of rat placenta and syncytiotrophoblast cell lines, TR-TBT2006
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Wada, M, Horieya, S, Kose, N, SaiY, Wakayama, T, Nakashima, E
Organizer
2006 AAPS Annual Meeting and Exposition
Place of Presentation
San Antonio, TX, USA
Year and Date
2006-11-02
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[Presentation] Clarification of intracellular localization of CLP36 and ezrin in syncytiotrophoblast and their relevance to polar distribution of transport.ers in the placenta2006
Author(s)
Sai Y, Horieya S, Wada M, Lee K-E, Iizasa H, Kose N, Wakayama T, Tamura A, Tsukita S, Kang Y-S, Nakashima E.
Organizer
The 1st Asia Pacific ISSX Meeting
Place of Presentation
Jeju,Korea
Year and Date
2006-05-25
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[Presentation] Clarification of intracellular localization of CLP36 and ezrin in syncytiotrophoblast and their relevance to polar distribution of transporters in the placenta2006
Author(s)
Sai, Y, Horieya, S, Wada, M, Lee, K-E, Iizasa, H, Kose, N, Wakayama, T, Tamura, A, Tsukita, S, Kang, Y-S, Nakashima, E
Organizer
The 1st Asia pacific ISSX Meeting
Place of Presentation
Jeju, Korea
Year and Date
2006-05-25
Description
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[Presentation] Screening of nucleoside drug interaction in rat placenta cell line, TR-TBT 18d-12006
Author(s)
Chishu, T, Sai, Y, Kose, N, Koma, T, Nakashima, E
Organizer
The 1st Asia pacific ISSX Meeting
Place of Presentation
Jeju, Korea
Year and Date
2006-05-25
Description
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[Presentation] Influx mechanism of 2', 3'-dideoxyinosine (ddI) to a conditionally immortalized syncytioprophoblast cell line, TR-TBT2006
Author(s)
Sato, K, Sai, Y, Kose, N, Koma, T, Nakashima, E
Organizer
The 1st Asia pacific ISSX Meeting
Place of Presentation
Jeju, Korea
Year and Date
2006-05-25
Description
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