Hepatocyte Nuclear Factor 6 Activates the Transcription of <i>CYP3A4</i> in Hepatocyte-like Cells Differentiated from Human Induced Pluripotent Stem Cells
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- SASAKI Takamitsu
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
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- TAKAHASHI Shogo
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
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- NUMATA Yoshihiro
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
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- NARITA Masayo
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
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- TANAKA Yutaka
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
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- KUMAGAI Takeshi
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
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- KONDO Yuki
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University
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- MATSUNAGA Tamihide
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University
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- OHMORI Shigeru
- Department of Molecular Pharmacology, Shinshu University Graduate School of Medicine Department of Pharmacy, Shinshu University Hospital
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- NAGATA Kiyoshi
- Department of Environmental and Health Science, Tohoku Pharmaceutical University
Bibliographic Information
- Other Title
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- Hepatocyte Nuclear Factor 6 Activates the Transcription of CYP3A4 in Hepatocyte-like Cells Differentiated from Human Induced Pluripotent Stem Cells
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Abstract
Human induced pluripotent stem cells (iPSCs) are a valuable source of hepatocytes for applications in drug metabolism studies. However, the current protocols for generating iPSC-derived hepatocyte-like cells (iPSHCs) are still very inefficient, and iPSHCs do not have sufficient hepatocyte-specific features, which include expression of a series of hepatocyte-specific genes, such as those encoding cytochrome P450 (CYP). In this study, we investigated whether introduction of human hepatocyte nuclear factor 6 (HNF6) could modulate the expression of CYP3A4 and other CYP genes in iPSHCs as well as in HepG2 cells, a fetal liver cell line (HFL cells), and in hepatocytes. CYP3A4 mRNA could be detected in iPSHCs, but the expression level was very low compared with those in HepG2 cells and hepatocytes. However, the CYP3A4 mRNA levels markedly increased on introduction of HNF6 and reached one-tenth of those in hepatocytes. We also found that HNF6 introduction increased CYP3A4 gene transcription in HFL cells and HepG2 cells, which have features similar to those of fetal hepatocyte-like cells; however, it did not affect CYP3A4 mRNA expression in hepatocytes. These results suggest that HNF6 plays an important role in the gene regulation of CYP3A4 during development from the fetal period to the postnatal period.<br>
Journal
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- Drug Metabolism and Pharmacokinetics
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Drug Metabolism and Pharmacokinetics 28 (3), 250-259, 2013
The Japanese Society for the Study of Xenobiotics