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Research ArticleArticle

Hepatocyte Nuclear Factor 4α Regulates Expression of the Mouse Female-Specific Cyp3a41 Gene in the Liver

Wattanaporn Bhadhprasit, Tsutomu Sakuma, Yuki Kawasaki and Nobuo Nemoto
Drug Metabolism and Disposition March 2011, 39 (3) 490-497; DOI: https://doi.org/10.1124/dmd.110.035980
Wattanaporn Bhadhprasit
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Tsutomu Sakuma
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Yuki Kawasaki
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Nobuo Nemoto
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Abstract

CYP3A41 is a female-specific cytochrome P450 in mouse liver. A putative hepatocyte nuclear factor 4α (HNF4α)-binding site was found at −99/−87 in the promoter of Cyp3a41 by reporter assays performed in the hepatocytes of female mice. Cotransfection of an 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 in 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 in 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 livers of mice.

Footnotes

  • This work was supported in part by the Japanese Ministry of Education, Culture, Sports, Science, and Technology; and the Smoking Research Foundation.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035980.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    GH
    growth hormone
    HNF
    hepatocyte nuclear factor
    PCR
    polymerase chain reaction
    ChIP
    chromatin immunoprecipitation
    Luc
    luciferase
    bp
    base pairs
    EMSA
    electrophoretic mobility shift assay
    PIPES
    1,4-piperazinediethanesulfonic acid
    RT
    reverse transcription
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    ANOVA
    analysis of variance
    DR
    direct repeat
    H3K4
    histone-3-lysine-4
    H3K27
    histone-3-lysine-27
    H3K4me2
    histone-3-lysine-4 dimethylation
    H3K27me3
    histone-3-lysine-27 trimethylation.

  • Received August 19, 2010.
  • Accepted November 18, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (3)
Drug Metabolism and Disposition
Vol. 39, Issue 3
1 Mar 2011
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Research ArticleArticle

Hepatocyte Nuclear Factor 4α Regulates Expression of the Mouse Female-Specific Cyp3a41 Gene in the Liver

Wattanaporn Bhadhprasit, Tsutomu Sakuma, Yuki Kawasaki and Nobuo Nemoto
Drug Metabolism and Disposition March 1, 2011, 39 (3) 490-497; DOI: https://doi.org/10.1124/dmd.110.035980

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Research ArticleArticle

Hepatocyte Nuclear Factor 4α Regulates Expression of the Mouse Female-Specific Cyp3a41 Gene in the Liver

Wattanaporn Bhadhprasit, Tsutomu Sakuma, Yuki Kawasaki and Nobuo Nemoto
Drug Metabolism and Disposition March 1, 2011, 39 (3) 490-497; DOI: https://doi.org/10.1124/dmd.110.035980
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