Role of epigenetic regulation on female-predominant expression of drug-metabolizing enzyme CYP3A gene

2014 Fiscal Year Final Research Report

• Project/Area Number: 23590172
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: University of Toyama
• Principal Investigator: SAKUMA TSUTOMU 富山大学, 大学院医学薬学研究部(薬学), 准教授 (30250468)
• Co-Investigator(Kenkyū-buntansha): KAWASAKI Yuki 富山大学, 大学院医学薬学研究部(薬学), 助教 (30432107)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Keywords: 性差 / CYP / 発現調節 / マウス / エピジェネティック

Outline of Final Research Achievements

Some of CYP3A genes including human CYP3A4 and mouse Cyp3a41 express female-predominantly. The objective of this study is to clarify the mechanisms, especially epi-genetic manner, for female-predominant expression. Our study demonstrated that female-dominant binding of HNF4a to the promoter (-99/-87) was involved in female specific expression of mouse Cyp3a41 gene. CHART-PCR analysis demonstrated that the chromatin prepared from female mouse hepatocytes was more relaxed than that from male hepatocytes. It is, therefore, likely that this difference is a cause of the female-dominant binding of HNF4a on Cyp3a41 gene. Reporter gene assay demonstrated that COUP-TFII and HNF4a interact in a synergic manner on Cyp3a41 gene in female hepatocytes. Thus, sex difference in chromatin structure and synergistic interaction between HNF4a and COUP-TFII may contribute to the female-specific expression of Cyp3a41 in the livers of mice.

Free Research Field

薬物代謝学