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Hepatocytes with a phenotype of substantial CYP3A4 induction generated from drug-associated fulminant hepatitis-derived induced pluripotent stem cells

Kenta Ite, Masashi Toyoda, Saeko Yoshioka, Takaaki Yukitake, Mayu Yamazaki-Inoue, Kuniko Tatsumi, Hidenori Akutsu, Hiroshi Nishina, Tohru Kimura, Naoko Ohtani, Atsuko Nakazawa, Mureo Kasahara, Akihiro Umezawa
doi: https://doi.org/10.1101/2021.11.30.470519
Kenta Ite
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
2Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-0034, Japan
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Masashi Toyoda
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
3Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
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Saeko Yoshioka
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
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Takaaki Yukitake
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
4Department of Applied Biological Science, Tokyo University of Science, Tokyo, 162-8601, Japan
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Mayu Yamazaki-Inoue
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
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Kuniko Tatsumi
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
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Hidenori Akutsu
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
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Hiroshi Nishina
5Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-0034, Japan
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Tohru Kimura
6Department of BioSciences, Kitasato University School of Science, Kanagawa, 252-0373, Japan
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Naoko Ohtani
4Department of Applied Biological Science, Tokyo University of Science, Tokyo, 162-8601, Japan
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Atsuko Nakazawa
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
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Mureo Kasahara
7Organ Transplantation Center, National Center for Child Health and Development, Tokyo, 157-8535, Japan
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Akihiro Umezawa
1Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan
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  • For correspondence: umezawa@1985.jukuin.keio.ac.jp
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ABSTRACT

Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4). Hepatocytes are often employed to evaluate drug-mediated CYP3A4 induction, but the variation between different cell lots is an issue that needs to be solved. Only a limited number of immortalized hepatocyte cell lines have been reported to date. In this study, we describe the successful generation of hepatocytes from disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with fulminant hepatitis (FH-iPSCs). To examine the CYP3A4 induction potential, FH-iPSCs were induced into hepatocytes. Drug-mediated induction testing revealed that HepaKI exhibited a 57.2-fold increase in CYP3A4 after exposure to rifampicin, relative to control cells. These results suggest that FH-iPSCs are a preferred cell source for in vitro CYP3A4 induction assays.

Competing Interest Statement

AU designed experiments. KI, MT, SY, and TY performed experiments. KI and AU analyzed data. KI, MYI, KT, AN, and MK contributed reagents, materials and analysis tools. MT, HA, HN, TK, and NO discussed the data and manuscript. AU and KI wrote this manuscript.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 30, 2021.
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Hepatocytes with a phenotype of substantial CYP3A4 induction generated from drug-associated fulminant hepatitis-derived induced pluripotent stem cells
Kenta Ite, Masashi Toyoda, Saeko Yoshioka, Takaaki Yukitake, Mayu Yamazaki-Inoue, Kuniko Tatsumi, Hidenori Akutsu, Hiroshi Nishina, Tohru Kimura, Naoko Ohtani, Atsuko Nakazawa, Mureo Kasahara, Akihiro Umezawa
bioRxiv 2021.11.30.470519; doi: https://doi.org/10.1101/2021.11.30.470519
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Hepatocytes with a phenotype of substantial CYP3A4 induction generated from drug-associated fulminant hepatitis-derived induced pluripotent stem cells
Kenta Ite, Masashi Toyoda, Saeko Yoshioka, Takaaki Yukitake, Mayu Yamazaki-Inoue, Kuniko Tatsumi, Hidenori Akutsu, Hiroshi Nishina, Tohru Kimura, Naoko Ohtani, Atsuko Nakazawa, Mureo Kasahara, Akihiro Umezawa
bioRxiv 2021.11.30.470519; doi: https://doi.org/10.1101/2021.11.30.470519

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