Nishimura, Tomohiro

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 薬剤学講座 （Shiba-Kyoritsu）

Position

Associate Professor
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Career 【 Display / hide 】

  • 2007.04
    -
    2008.03

    共立薬科大学, 助手

  • 2008.04
    -
    2013.03

    慶應義塾大学, 薬学部, 助教

  • 2011.09
    -
    2012.08

    Mount Sinai School of Medicine, Visiting Scientist

  • 2014.04
    -
    2017.03

    慶應義塾大学, 薬学部, 専任講師

  • 2017.04
    -
    Present

    慶應義塾大学, 薬学部, 准教授

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Academic Background 【 Display / hide 】

  • 2007.03

    Kanazawa University

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士（薬学）, Kanazawa University, Coursework, 2007.03

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Licenses and Qualifications 【 Display / hide 】

  • 甲種危険物取扱者, 2000.12

  • 薬剤師, 2004.04

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Books 【 Display / hide 】

  • 今日のOTC薬.

    中島恵美., 南江堂, 東京, 2009.04

    Scope: 1-624

  • 今日のOTC薬.

    Emi Nakashima, Akihiko Ito., 南江堂, 東京, 2009.03

    Scope: 374-379

  • トランスポーター科学最前線. 血液胎盤関門トランスポーターの機能.

    中島恵美, 崔吉道, 西村友宏., 京都/京都廣川書店, 2008.02

    Scope: 135-154

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Papers 【 Display / hide 】

  • Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake

    Nishimura T., Sano Y., Takahashi Y., Noguchi S., Uchida Y., Takagi A., Tanaka T., Katakura S., Nakashima E., Tachikawa M., Maruyama T., Terasaki T., Tomi M.

    Journal of Pharmaceutical Sciences （Journal of Pharmaceutical Sciences)  108 （ 12 ） 3917 - 3922 2019.12

    ISSN  00223549

    　View Summary

    © 2019 The Authors The aims of this study are to quantify the protein levels of nucleoside transporters in placental microvillous membranes (MVMs) and to clarify the contributions of these transporters to ribavirin uptake at the placental barrier. Placental MVMs of human and rat expressed equilibrative nucleoside transporter (ENT) 1 protein, whereas the expression of ENT2 protein was obscure. Maternal-to-fetal transfer of [3H]ribavirin in rats was much higher than that of [14C]sucrose. The uptake of [3H]ribavirin by rat placental trophoblast TR-TBT 18 d-1 cells, which functionally express both ENT1 and ENT2 proteins, was saturable, and was significantly inhibited by 0.1 μM nitrobenzylthioinosine, which selectively abolishes ENT1-mediated uptake. Dipyridamole at 10 μM is capable of inhibiting ENT2 as well as ENT1, but a degree of inhibition by 10 μM dipyridamole on [3H]ribavirin uptake was not much different from that by 0.1 μM nitrobenzylthioinosine (ENT1-specific inhibitor). Therefore, ENT2 may contribute little to [3H]ribavirin uptake by these cells. Rat ENT1 cRNA-injected oocytes showed increased [3H]ribavirin uptake compared with water-injected oocytes, while rat ENT2 cRNA-injected oocytes did not. In conclusion, ENT1 protein expressed in placental MVMs appears to play a predominant role in the uptake of ribavirin.

  • LAT1-Targeting Thermoresponsive Liposomes for Effective Cellular Uptake by Cancer Cells

    Maekawa-Matsuura M., Fujieda K., Maekawa Y., Nishimura T., Nagase K., Kanazawa H.

    ACS Omega （ACS Omega)  4 （ 4 ） 6443 - 6451 2019.04

    　View Summary

    © 2019 American Chemical Society. L-type amino acid transporter 1 (LAT1) is a transporter that is more highly expressed in cancer cells compared with normal cells. In the present study, liposomes, composed of egg phosphatidylcholine (EPC) and dioleoyl phosphatidylethanolamine, were modified with LAT1-targeting thermoresponsive polymer, l-tyrosine-conjugated poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)). The cellular uptake of the prepared LAT1-targeting liposomes was evaluated using HeLa cells as a cancer cell model. At temperatures above the polymer's lower critical solution temperature, uptake of the liposomes into cells was observed because the polymer at the liposome surface became hydrophobic and interacted with the cell membrane. Flow cytometry analysis suggested that l-tyrosine-P(NIPAAm-co-DMAAm)-liposomes exhibited markedly increased cellular uptake by HeLa cells compared with that of liposomes not modified with l-tyrosine. This result indicated that cellular uptake of liposomes can be enhanced by the affinity between l-tyrosine and the LAT1 of HeLa cells. The developed functional liposomes, which exhibit both thermoresponsive and LAT1-targeting properties, would be appropriate for temperature-modulated drug delivery and imaging with good targeting ability.

  • Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line

    Takahashi Y., Nishimura T., Higuchi K., Noguchi S., Tega Y., Kurosawa T., Deguchi Y., Tomi M.

    Pharmaceutical Research （Pharmaceutical Research)  35 （ 12 ）  2018.12

    ISSN  07248741

    　View Summary

    © 2018, The Author(s). Purpose: The anti-epileptic drug pregabalin crosses the blood-brain barrier (BBB) in spite of its low lipophilicity. This study was performed to determine whether L-type amino acid transporters (LAT1/SLC7A5 and LAT2/SLC7A8) contribute to the uptake of pregabalin. Methods: Pregabalin uptake by LATs-transfected HEK293 cells or hCMEC/D3 cells, an in vitro human BBB model, was measured by LC-MS/MS analysis. Expression of LAT1 mRNA in hCMEC/D3 cells was determined by quantitative RT-PCR analysis. Results: Overexpression of LAT1, but not LAT2, in HEK293 cells significantly increased the cellular uptake of pregabalin, and the LAT1-mediated uptake was saturable with a Km of 0.288 mM. LAT1-mediated amino acid uptake was inhibited specifically and almost completely in the presence of 1 mM pregabalin. The uptake of pregabalin by hCMEC/D3 cells was sodium-independent, saturable (Km = 0.854 mM), and strongly inhibited by large amino acids at 1 mM, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, a specific system L inhibitor, at 1 mM and by JPH203, a LAT1-selective inhibitor, at 10 μM. Pregabalin uptake in hCMEC/D3 cells was also decreased by 75% by the silencing of LAT1 gene using LAT1 siRNA. Conclusions: Our results indicate that LAT1, but not LAT2, recognizes pregabalin as a substrate. It is suggested that LAT1 mediates pregabalin transport at the BBB.

  • LAT1-targeting thermoresponsive fluorescent polymer probes for cancer cell imaging

    Matsuura M., Ohshima M., Hiruta Y., Nishimura T., Nagase K., Kanazawa H.

    International Journal of Molecular Sciences （International Journal of Molecular Sciences)  19 （ 6 ）  2018.06

    ISSN  16616596

    　View Summary

    © 2018 by the authors. Licensee MDPI, Basel, Switzerland. L-type amino acid transporter 1 (LAT1) is more highly expressed in cancer cells compared with normal cells. LAT1 targeting probes would therefore be a promising tool for cancer cell imaging. In this study, LAT1-targeting thermoresponsive fluorescent polymer probes based on poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)) were synthesized and their affinity for LAT1 was evaluated. The synthesized polymer probes interacted with LAT1 on HeLa cells, and inhibition of L-[3 H]-leucine, one of the substrates for LAT1 uptake, was investigated. L-Tyrosine-conjugated P(NIPAAm-co-DMAAm) inhibited the uptake of L-[3 H]-leucine, while P(NIPAAm-co-DMAAm) and L-phenylalanine-conjugated P(NIPAAm-co-DMAAm) did not. This result indicated that L-tyrosine-conjugated polymer has a high affinity for LAT1. The fluorescent polymer probes were prepared by modification of a terminal polymer group with fluorescein-5-maleimide (FL). Above the polymer transition temperature, cellular uptake of the polymer probes was observed because the polymers became hydrophobic, which enhanced the interaction with the cell membrane. Furthermore, quantitative analysis of the fluorescent probe using flow cytometry indicated that L-tyrosine-conjugated P(NIPAAm-co-DMAAm)-FL shows higher fluorescence intensity earlier than P(NIPAAm-co-DMAAm)-FL. The result suggested that cellular uptake was promoted by the LAT1 affinity site. The developed LAT1-targeting thermoresponsive fluorescent polymer probes are expected to be useful for cancer cell imaging.

  • Hypotaurine is a substrate of GABA transporter family members GAT2/Slc6a13 and TAUT/Slc6a6

    Nishimura T., Higuchi K., Yoshida Y., Sugita-Fujisawa Y., Kojima K., Sugimoto M., Santo M., Tomi M., Nakashima E.

    Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin)  41 （ 10 ） 1523 - 1529 2018

    ISSN  09186158

    　View Summary

    © 2018 The Pharmaceutical Society of Japan. Hypotaurine is a precursor of taurine and a physiological antioxidant that circulates in adult and fetal plasma. The purpose of the present study was to clarify whether hypotaurine is a substrate of Slc6a/gammaaminobutyric acid (GABA) transporter family members. Radiolabeled hypotaurine was synthesized from radiolabeled cysteamine and 2-aminoethanethiol dioxygenase. The uptakes of [3H]GABA, [3H]taurine, and [14C]hypotaurine by HEK293 cells expressing mouse GAT1/Slc6a1, TAUT/Slc6a6, GAT3/Slc6a11, BGT1/ Slc6a12, and GAT2/Slc6a13 were measured. TAUT and GAT2 showed strong [14C]hypotaurine uptake activity, while BGT1 showed moderate activity, and GAT1 and GAT3 showed slight but significant activity. Mouse TAUT and GAT2 both showed Michaelis constants of 11 μM for hypotaurine uptake. GAT2-expressing cells pretreated with hypotaurine showed resistance to H2O2-induced oxidative stress. These results suggest that under physiological conditions, TAUT and GAT2 would be major contributors to hypotaurine transfer across the plasma membrane, and that uptake of hypotaurine via GAT2 contributes to the cellular resistance to oxidative stress.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Mother-to-fetus transfer of antiviral drugs and the involvement of transporters at the placental barrier.

    Tomi M, Nishimura T, Nakashima E*.

    J Pharm Sci (WILEY-BLACKWELL)  100(9)   3708-3718 2011.09

    Introduction and explanation (scientific journal), Joint Work

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Presentations 【 Display / hide 】

  • Hypotaurineおよびその供給因子の胎盤組織内分布

    斉藤慶、西村友宏、中島恵美 、登美斉俊

    日本薬学会第137年会 (仙台) , 2017.03

  • 胎盤を介した胎児からのクレアチニン排出輸送機構の解析

    山下稔貴、西村友宏、中島恵美 、登美斉俊

    日本薬学会第137年会 (仙台) , 2017.03

  • げっ歯類合胞体栄養膜細胞層におけるMDR1およびBCRPの局在

    登美斉俊、明石知也、高木良也、中島恵美、西村友宏

    第24回日本胎盤学会学術集会 (和歌山) , 2016.11

  • SLC6Aファミリーによるヒポタウリン輸送と酸化ストレスに対する細胞保護作用

    西村友宏、　樋口慧、中島恵美、登美斉俊

    第38回生体膜と薬物の相互作用シンポジウム (名古屋) , 2016.11

  • ヒトOAT4 (SLC22A11) 遺伝子の胎盤特異的転写開始点の同定と転写活性に及ぼす影響

    古郡加奈子、野口幸希、篠原裕美、阿部真希子、西村友宏、中島恵美、登美斉俊

    日本薬物動態学会第31年会　松本 (松本) , 2016.10

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 降圧薬同効薬間の有害事象報告頻度比較分析に基づく妊娠高血圧症治療薬開拓

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西村　友宏, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • Adverse fetal effect of thalidomide via semen

    2016.04
    -
    2017.03

    日本医療研究開発機構（AMED）, Research on Regulatory Science of Pharmaceuticals and Medical Devices, 西村友宏, Principal Investigator

  • Functional expression of sensing foctors against maternal osmotic stress in the placenta

    2015.04
    -
    2018.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西村　友宏, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • エズリンを基軸とする胎児発育制御分子ネットワーク

    2014.04
    -
    2015.03

    上原記念生命科学財団

  • Gene network analysis of placental function regulators and a seed gene, ezrin

    2013.04
    -
    2015.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西村　友宏, Grant-in-Aid for Early-Carrer Scientists (B), Research grant, Principal Investigator

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Awards 【 Display / hide 】

  • 崔 吉道, 樋口 慧, 和田真実, 巨勢典子, 西村友宏, 田村 淳, 月田早智子, 若山友彦, 中島恵美., 2007.06, トランスポーター研究会, ラット胎盤におけるezrinの発現変動とP-glycoproteinおよびGLUT1細胞内局在への影響.

    Type of Award： Awards of National Conference, Council and Symposium

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Courses Taught 【 Display / hide 】

  • BIOPHARMACEUTICS

    2019, Outside own faculty (within Keio)

  • PHARMACOKINETICS

    2019, Outside own faculty (within Keio)

  • APPLIED PHARMACOKINETICS

    2019, Spring Semester, Within own ｆaculty

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2020

  • SEMINAR: (PHARMACEUTICS)

    2020

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