Abstract

CYP3A41 is a female-specific cytochrome P450 in mouse liver. A putative HNF4α-binding site was found at -99/-87 in the promoter of Cyp3a41 by reporter assays performed in the hepatocytes of females. Cotransfection of a HNF4α expression plasmid significantly increased transcription of the reporter gene. Although electrophoretic mobility shift assays with liver nuclear extracts did not show a sex-related difference, chromatin immunoprecipitation (ChIP) assays showed that larger amounts of HNF4α bound to Cyp3a41 in female than male mice. A relation between the amount of HNF4α on the Cyp3a41 gene and mRNA expression was observed in hepatic tissue sets which differ in mRNA expression depending on the sex, age or endocrine status of mice. The degree of histone-3-lysine-4 dimethylation and histone-3-lysine-27 trimethylation around the HNF4α-binding site was higher in females and males, respectively. Moreover, the ChIP assay indicated greater acetylation of histone-4-lysine-8 of the Cyp3a41 chromatin in females than males. HNF4α plays an important role in the transcriptional activation of the Cyp3a41 gene and a sex difference in chromatin structure may contribute to the female-specific expression of Cyp3a41 in the liver of mice.