Study of periodic change of the expression of constitutively expressing drug-metabolizing cytochrome P450 genes
| Project/Area Number |
18590136
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | University of Toyama |
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Principal Investigator |
SAKUMA Tsutomu University of Toyama, Graduate School of Medicine and Pharmaceutical Sciences, Associate Professor (30250468)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,160,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | circadian rhythm / estrous cycle / CYP3A41 / CYP3A44 / mouse / HNF4α |
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| Research Abstract |
In this Study, periodical change of the constitutive expression of Cyp3a genes in the liver of female mice was examined. Among five mouse Cyp3a genes examined, some genes expressing female-specifically in the liver showed estrous cycle- and time- dependent modulation. Expression of Cyp3a41 and Cyp3a16 genes in vaginal estrus is 2-3-fold higher than that in proestrus. Expression of both genes in midnight was 2-fold higher than that in noon, and it was well correlated to the change of HNF4alpha, one of liver-enriched nuclear transcription factors. Reporter gene assay using female mouse hepatocytes in primary culture and 5'-flanking region of the Cyp3a41 gene indicated that the element involved in constitutive- and glucocorticoid hormone-inducible expression locates within -1631+61 region. In this region, one predictive HNF4alpha binding sequence was found, and mutation of the site caused reduction of glucocorticoid hormone-inducible expression as well as constitutive expression In order to confirm this result, in vivo reporter gene assay using the hydrodynamic DNA delivery was carried out. As a result, reporter activity driven from -1631+61 region was observed in female mice, and not in male mice. Mutation at the predictive HNF4alpha binding site completely suppressed reporter gene activity. Transfection of the expression plasmid for HNF4alpha into hepatocytes caused expression of Cyp3a41 gene, more prominently in female hepatocytes, and this expression was enhanced by simultaneous treatment with synthetic glucocorticoid hormone dexamethasone. ChIP assay indicated that HNF4alpha bound to the Cyp3a41 gene promoter, more remarkable in female hepatocytes. In conclusion, this study revealed that HNF4 alpha binds to proximal region of the Cyp3a41 gene promoter to activate transcription, and HNF4 alpha might be a factor to cause circadian modulation of Cyp3a41 gene expression.
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Report
(3 results)
Research Products
(26 results)
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[Journal Article] Involvement of glucocorticoid receptor and pregnane X receptor in the regulation of mouse CYP3A44 female- predominant expression by glucocorticoid hormone2007
Author(s)
Wattanaporn, Bhadhprasit, Tsutomu, Sakuma, Nobuyuki, Hatakeyama, Masahiro, Fuwa, Kaori, Kitajima, Nobuo, Nemoto
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Journal Title
Drug Metabolism and Disposition 35
Pages: 1880-1885
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver2006
Author(s)
Kanokwan, Jarukamjorn, Tsutomu, Sakuma, Atika, Jaruchotikamol, Yukako, Ishino, Miki, Oguro, Nobuo, Nemoto
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Journal Title
Toxicology 219
Pages: 97-105
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Role of HNF4 alpha in regulation mechanism for constitutive expression of female-specific mouse Cyp3a41 gene in livers2007
Author(s)
Yukihiro, Furusawa, Tsutomu, Sakuma, Wattanaporn, Bhadhprasit, Tadahiro, Hashita, Kimiko, Miyauchi, Kaoru, Abe, Yasuyuki, Mukai, Nobuo, Nemoto
Organizer
117th meeting of the Hokuriku-branch of the Pharmaceutical Society of Japan
Place of Presentation
Kanazawa
Year and Date
2007-11-11
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Role of HNF4 alpha in constitutive expression of Cyp3a41 gene in female mouse livers2007
Author(s)
Yukihiro, Furusawa, Tsutomu, Sakuma, Shin-ichi, Ueno, Wattanaporn, Bhadhprasit, Tadahiro, Hashita, Kaoru, Abe, Nobuo, Nemoto
Organizer
BMB2007
Place of Presentation
Yokohama
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Effects of growth hormone treatment on the expression of Cyp genes in mouse livers2006
Author(s)
Tsutomu, Sakuma, Kanokwan, Jarukamjorn, Atika, Jaruchotikamol, Yukako, Ishino, Miki, Oguro, Nobuo Nemoto
Organizer
126th annual meeting of the Pharmaceutical Society of Japan
Place of Presentation
Sendai
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of Cyp3a41 and Cyp3a44 gene expression mediated by glucocorticoid receptor2006
Author(s)
Wattanaporn, Bhadhprasit, Tsutomu, Sakuma, Masahiro, Fuwa, Shin-ichi, Ueno, Kaori, Kitajima, Nobuo, Nemoto
Organizer
21th JSSX meeting
Place of Presentation
Tokyo
Description
「研究成果報告書概要(欧文)」より
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