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

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.