Prediction system of risk assessments by change the drug metabolism activity in placenta for pregnancy
| Project/Area Number |
17K08426
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Showa Pharmaceutical University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 肝細胞 / チトクロムP450 / サイトカイン / 長期間維持培地 / 培養肝細胞 / iPS細胞 / 3次元培養法 / 初代培養肝細胞 / BeWo細胞 / P450 / 酵素誘導 / ヒト肝由来HepaＲG cells / ips細胞 / 薬物透過性 / iPS / 培養時間 / 培地組成 / 薬学 |
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| Outline of Final Research Achievements |
Hepatocyte-like cells differentiated from human induced pluripotent stem (iPS) cells are of great interest for applications in pharmacological research. For drug metabolism testing, commercially available hepatocytes derived from human iPS cells are generally recommended to be used 1week after seeding on plates. In this study, however, after 3-4 weeks of culture according to the manufacturer’s instructions, human cytochromeP450(P450)2C9 and 2C19-depended diclofenac 4’-hydroxylation and omeprazole 5-hydroxylation activities of the iPS-derived hepatocytes has significantly increased above the activities at １week and had reached levels similar to those in HepaRG cells ,a human hepatocyte like celll line. Our findings that the hepatic functios of human iPS-derived hepatocytes were enhanced by 3 weeks of simple culture could facilitate the use of these cells for drug metabolism and toxicity tesing.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、創薬や化学物質の毒性評価に汎用されているヒト肝細胞であるが、良質な細胞の供給に関しては問題がある。細胞の代謝酵素活性には常にドナーの肝の代謝能力に影響を受けるためロットによる差が大きいと言われている。心筋などへの分化誘導が可能となっているiPS細胞を形態だけでなく機能を有した状態で分化させる条件検討した本研究の成果は、多くの肝細胞の研究へのiPS細胞の導入に役立つものと考えている。また、各種ガイドラインでの細胞を用いた評価系の確立について、ヒト肝細胞からさらに1つの候補としてiPS細胞を提案し、ヒト肝細胞の十分な供給を可能にする社会的意義につながる。
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Report
(4 results)
Research Products
(15 results)
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[Journal Article] Oxidation of Flavone, 5-Hydroxyflavone, and 5,7-Dihydroxyflavone to Mono-, Di-, and Tri-Hydroxyflavones by Human Cytochrome P450 Enzymes2019
Author(s)
Nagayoshi, H. Murayama, N. Kakimoto, K. Tsujino, M. Takenaka, S. Katahira, J. Lim, Y. R. Kim, D. Yamazaki, H. Komori, M. Guengerich, F. P. Shimada, T.
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Journal Title
Chemical Research in Toxicology
Volume: 32
Issue: 6
Pages: 1268-1280
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Assessment of multiple cytochrome P450 activities in metabolically inactivated human liver microsomes and roles of P450 2C isoforms in reaction phenotyping studies2018
Author(s)
Shimura, K., Ishii, Y., Takada, M., Uno, Y., Utoh, M., Iwasaki, K., and Yamazaki, H.
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Journal Title
Biopharm. Drug Dispos.
Volume: 39
Issue: 2
Pages: 115-121
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Molecular and functional characterization of UDP-glucuronosyltransferase 1A in cynomolgus macaques.2018
Author(s)
Uno, Y., Takahira, R., Murayama, N., Ishii, Y., Ikenaka, Y., Ishizuka, M., Yamazaki, H., and Ikushiro, S.
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Journal Title
Biochem. Pharmacol.
Volume: 155
Pages: 172-181
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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