Prediction system of risk assessments by change the drug metabolism activity in placenta for pregnancy

• Project/Area Number: 20K07139
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: Murayama Norie 昭和薬科大学, 薬学部, 講師 (90219949)
• Co-Investigator(Kenkyū-buntansha): 山崎 浩史 昭和薬科大学, 薬学部, 教授 (30191274) ; 清水 万紀子 昭和薬科大学, 薬学部, 准教授 (90307075)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ヒト幹細胞 / BeWo細胞 / 胎盤透過性 / レナリドマイド / 膜透過 / 胎盤細胞 / 肝細胞 / チトクロムP450 / 共存培養 / 胎盤 / 薬物代謝酵素 / 連結型培養手法 / 毒性評価

Outline of Research at the Start

創薬や化学物質の毒性評価では、動物実験の規制や種差の点で、ヒト培養細胞系を用いた評価系に期待が持たれている。母体が摂取した脂溶性の高い化学物質は胎盤を通過し、物質交換とともに胎児側に取り込まれ毒性発現の危険性がある。ヒト胎盤には各種薬物代謝酵素が存在しているが、妊娠期間中母体の外来性異物代謝活性の変動と胎盤透過後の体内動態を評価系する計が確立しておらず詳細な検討は行われていない。申請者は母体で代謝された化合物の胎盤透過前後の毒性発現について検討するために、肝臓と胎盤由来細胞を共存させ、胎盤透過率(Papp)から吸収量(ka)を予測し毒性を評価できる汎用性の高い簡易連結型培養手法を確立する。

Outline of Final Research Achievements

The quantitative extrapolation of the effective dose from in vitro to in vivo is of increasing importance. For developmental toxicity this requires scaling the in vitro observed dose-response characteristics to in vivo fetal exposure, in particular transplacental transfer. Transplacental transfer of toxicants can be studied with the use of the BeWo cell, an in vitro model mimicking in vivo transport of a chemical from maternal blood across a cell barrier into the embryo. In this system, hepatocyte cells are co-cultured with BeWo cells to investigate the effects in particular transplacental transfer. This system expect to contribute to a prediction in silico the physiological pharmacokinetics model (PBPK) to the toxicity of chemicals.

Academic Significance and Societal Importance of the Research Achievements

Trans wellを用いたヒト肝細胞と胎盤細胞の共培養系が構築出来たことは、母体が摂取した化合物は胎盤にどのような作用を示すのかを検討する上で、有効活用出来ると共に、その他の細胞の共培養による実験系を提案する事となった。また、生体内の関門である血液脳関門での化合物透過性評価に関して、比較検討した範囲では両者の間に相関性が認められたことから、脳関門透過性評価への応用が期待出来る。今後さらにデーター数を揃えることで、化合物の物性値とともに関門透過性で汎用可能な生理学的薬物動態学 (PBPK）モデルを作成し、薬物・外来性異物の毒性発現をin silicoで予測するのに貢献できる。

Research Products

• [Journal Article] Plasma concentration profiles for hepatotoxic pyrrolizidine alkaloid senkirkine in humans extrapolated from rat data sets using a simplified physiologically based pharmacokinetic model. (2022)
  • Author(s): Kamiya, Y., Miura, T., Kato, A., Murayama, N., Shimizu, M., and Yamazaki, H.
  • Journal Title: Drug Metab Bioanal Lett Volume: 15 Issue: 1 Pages: 64-69
  • DOI: 10.2174/1872312801666211220110055
  • Peer Reviewed
• [Journal Article] Cytochrome P450 2J Genes Are Expressed in Dogs, Cats, and Pigs, and Encode Functional Drug-Metabolizing Enzymes (2022)
  • Author(s): Uno Yasuhiro、Murayama Norie、Ijiri Moe、Kawaguchi Hiroaki、Yamato Osamu、Shiraishi Mitsuya、Asano Atsushi、Teraoka Hiroki、Mizukawa Hazuki、Nakayama Shouta M.M.、Ikenaka Yoshinori、Ishizuka Mayumi、Yamazaki Hiroshi
  • Journal Title: Drug Metabolism and Disposition Volume: 50 Issue: 11 Pages: 1434-1441
  • DOI: 10.1124/dmd.122.000930
  • Peer Reviewed
• [Journal Article] Low cerebrospinal fluid-to-plasma ratios of orally administered lenalidomide mediated by its low cell membrane permeability in patients with hematologic malignancies (2022)
  • Author(s): Daisuke Ogiya, Norie Murayama, Yusuke Kamiya, Rie Saito, Sawako Shiraiwa, Rikio Suzuki, Shinichiro Machida, Kei Tazume, Kiyoshi Ando, Hiroshi Yamazaki
  • Journal Title: Annals of Hematology Volume: 101 Issue: 9 Pages: 2013-2019
  • DOI: 10.1007/s00277-022-04893-w
  • Peer Reviewed
• [Journal Article] Combined Risk Assessment of Food-derived Coumarin with <i>in Silico</i> Approaches (2022)
  • Author(s): Yamada, T., Katsutani, N., Maruyama, T., Kawamura, T., Yamazaki, H., Murayama, N., Tong, W., Yamazoe, Y., and Hirose, A.
  • Journal Title: Food Safety Volume: 10 Issue: 3 Pages: 73-82
  • DOI: 10.14252/foodsafetyfscj.D-21-00015
  • ISSN: 2187-8404
  • Peer Reviewed
• [Journal Article] Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment (2022)
  • Author(s): Norie Murayama,Takashi Yamada,Yasushi Yamazoe
  • Journal Title: Food Safety Volume: 10 Issue: 4 Pages: 129-139
  • DOI: 10.14252/foodsafetyfscj.D-22-00008
  • ISSN: 2187-8404
  • Peer Reviewed
• [Journal Article] Liquid chromatography-tandem mass spectrometry analysis of oxidation of 2´-, 3´-, 4´-, and 6-hydroxyflavanones by human cytochrome P450 enzymes. (2021)
  • Author(s): Shimada, T., Nagayoshi, H., Murayama, N., Takenaka, S., Katahira, J., Kim, V., Kim, D., Komori, M., Yamazaki, H. ,Guengerich, F. P.
  • Journal Title: Xenobiotica Volume: 51 Issue: 2 Pages: 139-154
  • DOI: 10.1080/00498254.2020.1836433
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic variants of aldehyde oxidase (AOX) 1 in cynomolgus and rhesus macaques (2021)
  • Author(s): Uno Yasuhiro、Uehara Shotaro、Murayama Norie、Yamazaki Hiroshi
  • Journal Title: Xenobiotica Volume: 51 Issue: 4 Pages: 494-499
  • DOI: 10.1080/00498254.2021.1874564
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic activation and deactivation of dietary-derived coumarin mediated by cytochrome P450 enzymes in rat and human liver preparations (2021)
  • Author(s): Murayama, N., Yamazaki, H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 46 Issue: 8 Pages: 371-378
  • DOI: 10.2131/jts.46.371
  • NAID: 130008070939
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Refined CYP2E1 Template; system to decipher the ligand-interactions (2021)
  • Author(s): Yamazoe, Y., Murayama N., and Yoshinari, K.
  • Journal Title: Drug Metab Pharmacokinet. Volume: 41 Pages: 1-12
  • DOI: 10.1016/j.dmpk.2021.100413
  • NAID: 210000188781
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of cytochrome P450 2A6 in the oxidation of flavone, 4´-hydroxyflavone, and 4´-, 3´-, and 2´-methoxyflavones by human liver microsomes. (2021)
  • Author(s): Nagayoshi, H., Murayama, N., Takenaka, S., Kim, V., Kim, D., Komori, M., Yamazaki, H., Guengerich, F. P., and Shimada, T.
  • Journal Title: Xenobiotica Volume: 51 Issue: 9 Pages: 995-1009
  • DOI: 10.1080/00498254.2021.1950866
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models (2021)
  • Author(s): Miura Tomonori、Kamiya Yusuke、Uehara Shotaro、Murayama Norie、Shimizu Makiko、Suemizu Hiroshi、Yamazaki Hiroshi
  • Journal Title: Xenobiotica Volume: － Pages: 1-7
  • DOI: 10.1080/00498254.2021.1908643
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic variants of UDP-glucuronosyltransferases 1A1, 1A6, and 1A9 in cynomolgus and rhesus macaques (2020)
  • Author(s): Uno Yasuhiro、Mikami Takahiro、Tsukazaki Yasuko、Nakanishi Yasuharu、Murayama Norie、Ikushiro Shinichi、Tsusaki Hideshi、Yamazaki Hiroshi
  • Journal Title: Xenobiotica Volume: 51 Issue: 1 Pages: 115-121
  • DOI: 10.1080/00498254.2020.1810367
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular characterization of functional UDP-glucuronosyltransferases 1A and 2B in common marmosets (2020)
  • Author(s): Uno Yasuhiro、Uehara Shotaro、Inoue Takashi、Kawamura Shu、Murayama Norie、Nishikawa Miyu、Ikushiro Shinichi、Sasaki Erika、Yamazaki Hiroshi
  • Journal Title: Biochemical Pharmacology Volume: 172 Pages: 113748-113748
  • DOI: 10.1016/j.bcp.2019.113748
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Different roles of human cytochrome P450 2C9 and 3A enzymes in diclofenac 4'- and 5-hydroxylations mediated by metabolically inactivated human hepatocytes in previously transplanted chimeric mice. (2020)
  • Author(s): .Miura, T., Uehara, S., Shimizu, M., Murayama, N., Utoh, M., Suemizu, H., and Yamazaki, H.
  • Journal Title: Chem. Res. Toxicol. Volume: 33 Issue: 2 Pages: 634-639
  • DOI: 10.1021/acs.chemrestox.9b00446
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preference for O-demethylation reactions in the oxidation of 2 -, 3 -, and 4 -methoxyflavones by human cytochrome P450 enzymes. (2020)
  • Author(s): Nagayoshi, H., Murayama, N., Tsujino, M., Takenaka, S., Katahira, J., Kim, V., Kim, D., Komori, M., Yamazaki, H., Guengerich, F. P., and Shimada, T.
  • Journal Title: Xenobiotica Volume: 50 Issue: 10 Pages: 1158-1169
  • DOI: 10.1080/00498254.2020.1759157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity. (2020)
  • Author(s): .Kamiya, Y., Takaku, H., Yamada, R., Akase, C., Abe, Y., Sekiguchi, Y., Murayama, N., Shimizu, M., Kitajima, M., Shono, F., Funatsu, K., and Yamazaki, H.
  • Journal Title: Toxicol. Rep. Volume: 149 Pages: 149-154
  • DOI: 10.1016/j.toxrep.2020.01.004
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic profiles of coumarin in human plasma extrapolated from a rat data set with a simplified physiologically based pharmacokinetic model (2020)
  • Author(s): 47.Miura T, Kamiya Y, Hina S, Kobayashi Y, Murayama N, Shimizu M, Yamazaki H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 45 Issue: 11 Pages: 695-700
  • DOI: 10.2131/jts.45.695
  • NAID: 130007935150
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Presentation] イヌ肝と小腸に発現するチトクロム4503A分子種の同定とそれらの機能解析 (2022)
  • Author(s): 村山典恵、野田優太朗、軸屋志織、宇野泰広、山崎浩史現するチトクロム4503A分子種の同定とそれらの機能解析
  • Organizer: 日本薬学会第142年会
• [Presentation] 物質のヒト体内動態を規定する生理学的薬物動態モデル重要パラメータの予測と消化管吸収性推定の精緻化 (2022)
  • Author(s): 神矢 佑輔、佐藤 翼、森國 紗帆、内海 正義、三浦 智徳、村山 典恵、清水 万紀子、半田 健太郎、北島 正人、庄野 文章、山崎 浩史
  • Organizer: 日本薬学会第142年会
• [Presentation] CYP2C19の代謝キネティクスにおける*23変異アレルの影響とその基質間差の要因 (2021)
  • Author(s): 渡辺大智、粟田祐作、秋好健志、関博行、今岡鮎子、村山典恵、山崎浩史、下地みゆき、中村克徳、大谷壽一
  • Organizer: 医療薬学フォーラム