Relevance to bioactivation and toxicity of thalidomide, pomalidomide, and lenalidomide by human cytochrome P450 3A enzymes in cultured placental cells and humanized-liver mice
| Project/Area Number |
17K08425
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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) |
村山 典惠 昭和薬科大学, 薬学部, 講師 (90219949)
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: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | サリドマイド / ポマリドマイド / レナリドマイド / フタル酸エステル / 生理学的薬物動態 / 胎盤 / 肝 / 酵素誘導 / 代謝的活性化 / レナリドミド / ポマリドミド |
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| Outline of Final Research Achievements |
Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of thalidomide due to oxidation to 5-hydroxythalidomide and subsequent metabolic activation in livers. Human placental BeWo cells, cultured in the recommended media, also indicated detectable thalidomide 5-hydroxylation activities. Thalidomide significantly induced P450 3A4/3A5, 2B6, and pregnane X receptor (PXR) mRNA levels 2 to 3-fold. Activation of thalidomide to 5-hydroxythalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.
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| Academic Significance and Societal Importance of the Research Achievements |
In vitroで認められたヒト胎盤におけるP450 3A酵素の自己誘導を伴うサリドマイドの5-ヒドロキシサリドマイドへの活性化は、肝および胎盤が複雑に連携するin vivo状態でも起こりうることが推察された。肝集積を含む経口投与後の体内動態を記述するモデルを活用し、活性化と解毒のバランスを考慮の上、物質量と生体中濃度を双方向に予測しうることを明かにした。一般化学物質の経口吸収後の臓器移行性が、肝毒性などの臓器毒性発現に一部関与していることが推定された。
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Report
(4 results)
Research Products
(33 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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