Relevance to bioactivation and toxicity of thalidomide, pomalidomide, and lenalidomide by human cytochrome P450 3A enzymes in cultured placental cells and humanized-liver mice

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08425
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: YAMAZAKI Hiroshi 昭和薬科大学, 薬学部, 教授 (30191274)
• 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)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: サリドマイド / ポマリドマイド / レナリドマイド

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.

Free Research Field

薬物動態学

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。