Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells

Murata, Michika; Okada, Kentaro; Takahashi, Masaki; Ueyama-Toba, Yukiko; Ito, Sumito; Mizuguchi, Hiroyuki

doi:https://doi.org/10.1016/j.toxlet.2024.10.003

Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells

Murata, Michika; Okada, Kentaro; Takahashi, Masaki et al.

Toxicology Letters, 2024, 401, 158-169

アクセス数:740件（2025-08-16 08:31 集計）

固定URL: https://hdl.handle.net/11094/98590

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タイトル	Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells
著者	著者名 Murata, Michika
	著者名 Okada, Kentaro
	著者名 Takahashi, Masaki
	NRID 1000010904930 1000010904930 ORCID 0000-0002-3491-7955 0000-0002-3491-7955 researchmap permalink toba-y toba-y 著者名 Ueyama-Toba, Yukiko
	NRID 1000020728969 1000020728969 著者名 Ito, Sumito
	NRID 1000050311387 1000050311387 researchmap permalink read0165079 read0165079 Scopus Author ID 57195381326 57195381326 著者名 Mizuguchi, Hiroyuki
キーワード等	Caco-2 cells
	CES
	CYP3A4
	Drug metabolism
	UGT1A1
内容	Murata M., Okada K., Takahashi M., et al. Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells. Toxicology Letters 401, 158 (2024); https://doi.org/10.1016/j.toxlet.2024.10.003.
抄録	Caco-2 cells, a human colorectal adenocarcinoma cell line, are widely used to model small intestinal epithelial cells in the drug development process because they can predict drug absorption with high accuracy. However, Caco-2 cells have several issues. First, Caco-2 cells have little expression of cytochrome P450 3A4 (CYP3A4), which is a major drug-metabolizing enzyme in the human intestine. We previously developed Caco-2 cells whose expression of CYP3A4 can be controlled using doxycycline (Dox) (CYP3A4-Caco-2 cells) (Ichikawa et al., Sci. Rep, 2021). However, since the Tet-On system was used to regulate CYP3A4 expression in these cells, there was concern about drug-drug interactions. The second issue is that in the human small intestine, carboxylesterase 2 (CES2) is more highly expressed than carboxylesterase 1 (CES1), while in Caco-2 cells CES1 is more highly expressed. The third issue is the low level expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a phase II drug-metabolizing enzyme. In this study, we used genome-editing technology to establish CES1-knockout Caco-2 cells whose CYP3A4 and UGT1A1 expression can be regulated by the Tet-Off system. These cell lines would be useful in pharmaceutical researches, including intestinal toxicological studies, as an in vitro model for orally administered drugs.
出版者	Elsevier Ireland Ltd
収録物名	Toxicology Letters
巻(号)	401
ページ	158-169
刊行年月	2024-11-01
言語	英語
ハンドルURL	https://hdl.handle.net/11094/98590
PISSN	03784274
eISSN	18793169
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1016/j.toxlet.2024.10.003
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Toxicology Letters. 2024, 401, p. 158-169
DC.title	Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells
DC.creator	Murata, Michika
	Okada, Kentaro
	Takahashi, Masaki
	Ueyama-Toba, Yukiko
	Ito, Sumito
	Mizuguchi, Hiroyuki
DC.publisher	Elsevier Ireland Ltd
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-11-01
DC.identifier	https://doi.org/10.1016/j.toxlet.2024.10.003
DC.subject	Caco-2 cells
	CES
	CYP3A4
	Drug metabolism
	UGT1A1
DC.description	Murata M., Okada K., Takahashi M., et al. Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells. Toxicology Letters 401, 158 (2024); https://doi.org/10.1016/j.toxlet.2024.10.003.
DCTERMS.abstract	Caco-2 cells, a human colorectal adenocarcinoma cell line, are widely used to model small intestinal epithelial cells in the drug development process because they can predict drug absorption with high accuracy. However, Caco-2 cells have several issues. First, Caco-2 cells have little expression of cytochrome P450 3A4 (CYP3A4), which is a major drug-metabolizing enzyme in the human intestine. We previously developed Caco-2 cells whose expression of CYP3A4 can be controlled using doxycycline (Dox) (CYP3A4-Caco-2 cells) (Ichikawa et al., Sci. Rep, 2021). However, since the Tet-On system was used to regulate CYP3A4 expression in these cells, there was concern about drug-drug interactions. The second issue is that in the human small intestine, carboxylesterase 2 (CES2) is more highly expressed than carboxylesterase 1 (CES1), while in Caco-2 cells CES1 is more highly expressed. The third issue is the low level expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a phase II drug-metabolizing enzyme. In this study, we used genome-editing technology to establish CES1-knockout Caco-2 cells whose CYP3A4 and UGT1A1 expression can be regulated by the Tet-Off system. These cell lines would be useful in pharmaceutical researches, including intestinal toxicological studies, as an in vitro model for orally administered drugs.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	98590
citation_title	Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells
citation_author	Murata, Michika
	Okada, Kentaro
	Takahashi, Masaki
	Ueyama-Toba, Yukiko
	Ito, Sumito
	Mizuguchi, Hiroyuki
citation_publisher	Elsevier Ireland Ltd
citation_language	英語
citation_date	2024-11-01
citation_journal_title	Toxicology Letters
citation_volume	401
citation_firstpage	158
citation_lastpage	169
citation_doi	https://doi.org/10.1016/j.toxlet.2024.10.003
citation_public_url	https://hdl.handle.net/11094/98590

Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells

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