Journal
DRUG METABOLISM AND PHARMACOKINETICS
Volume 28, Issue 3, Pages 250-259Publisher
JAPANESE SOC STUDY XENOBIOTICS
DOI: 10.2133/dmpk.DMPK-12-RG-132
Keywords
CYP3A4; differentiation; hepatocytes; HNF6; induced pluripotent stem cells; liver-enriched transcription factors
Categories
Funding
- Ministry of Health, Labour and Welfare of Japan [22230301]
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities
- [23790193]
- Grants-in-Aid for Scientific Research [23790193, 22390028] Funding Source: KAKEN
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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.
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