Exploration of the mechanism by which regulate hepatocyte specific functions and development of high functional hepatocyte culture system.

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460088
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Nakamura Kazuaki 国立研究開発法人国立成育医療研究センター, 薬剤治療研究部, 室長 (80392356)
• Research Collaborator: Kyaw Htet Aung ; AIZAWA Kazuko
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 肝細胞培養系 / DNAメチル化

Outline of Final Research Achievements

In this study, we explored the mechanism by which regulate hepatocyte specific functions and developed high functional hepatocyte culture system. We found that inhibitor of DNA methyltransferase, zebularine, upregulates the expression of CYP genes in HepG2 cells through inhibiting DNA methyltransferase 1 (DNMT1) and double-stranded RNA dependent protein kinase (PKR). Whereas inhibition of either DNMT1 or PKR slightly upregulates CYP gene expression, combined inhibition of both DNMT1 and PKR markedly upregulates CYP gene expression. Furthermore, HepG2 cells treated with zebularine were more sensitive than control HepG2 cells to drug toxicity. Taken together, our results show that combined inhibition of DNMT1 and PKR in HepG2 cells leads to effective upregulation of expression of CYP genes, which is a novel mechanism, and also suggest that HepG2 cells treated with zebularine and thus having upregulated CYP gene expression may be useful for evaluating drug toxicity in vitro.

Free Research Field

実験薬理学・細胞生物学