Establishment of in vitro and in vivo models for human CES which promote rational development of ester-based prodrugs

2015 Fiscal Year Final Research Report

• Project/Area Number: 25293035
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Chiba University
• Principal Investigator: Chiba Kan 千葉大学, 薬学研究科(研究院), 教授 (40159033)
• Co-Investigator(Kenkyū-buntansha): IMAI Teruko 熊本大学, 薬学部, 教授 (70176478) ; HOSOKAWA Masakiyo 千葉科学大学, 薬学部, 教授 (70181500) ; KOBAYASHI Kaoru 千葉大学, 大学院薬学研究院, 准教授 (30255864) ; FURIHATA Tomomi 千葉大学, 大学院薬学研究院, 助教 (80401008)
• Co-Investigator(Renkei-kenkyūsha): KAZUKI Yasuhiro 鳥取大学, 医学研究院, 准教授 (90403401)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 薬物代謝 / 試験系 / プロドラッグ / CES

Outline of Final Research Achievements

Carboxylesterase (CES) plays important roles in ester-type prodrug activation. It has been known that CES isoform expression profile of Caco-2 cells, widely-used human intestine model cells, differs from that of the human intestine. Therefore, we aimed to develop Caco-2 cells possessing human intestinal CES expression profile. Utilizing short-hairpin RNA against human CES1 mRNA and human CES2 expression retroviral system, CES2/CES1-KD/Caco-2 cells were developed. As seen in the human intestine, the CES2/CES1-KD/Caco-2 cells showed activity of CES2 but not CES1. Moreover, the cells showed the high transepithelial electric resistance value, indicating that the cells retained tight junction function. To summarize, we have successfully established a new Caco-2 cells that show the human intestine-like CES isoform expression profile. Thus, the CES2/CES1-KD/Caco-2 cells are expected to be a useful tool for ester-type prodrug development.

Free Research Field

薬学