| Project/Area Number |
17590101
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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 |
Environmental pharmacy
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| Research Institution | Doshisha Women's College of Liberal Arts |
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Principal Investigator |
KIZU Ryoichi Doshisha Women's College of Liberal Arts, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (80143915)
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| Co-Investigator(Kenkyū-buntansha) |
HAYAKAWA Kazuichi Kanazawa University, Graduate School of Natural Science and Technology, Professor, 自然科学研究科, 教授 (40115267)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | polycyclic aromatic hydrocarbon / aryl hydrocarbon receptor / androgen receptor / signal cross-talk / CYP1A1 / real-time PCR / reporter assay / siRNA / CYP1A1 / 抗男性ホルモン作用 / タンパク複合体 / 免疫沈降 / 代謝物 / LNCaP細胞 |
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| Research Abstract |
Role of aryl hydrocarbon receptor (AhR) in the antiandrogenic activities of polycyclic aromatic hydrocarbons (PAHs) was studies in androgen responsive cell lines. Results obtained are as follows. 1. Antiandrogenic activities of metabolites of PAHs were weak, and therefore, the contribution of metabolites of PAHs is not significant. 2. Decrease in neither cellular androgen concentration nor androgen receptor (AR) expression level was caused by treatment with the antiandrogenic PAHs. 3. Formation of AR-AhR protein complex was induced by treatment with the antiandrogenic PAHs. 4. While DJ-1 is a protein that form a complex with AR and is involved in the control of androgenic action, the complex formation between DJ-1 and AR was not affected by treatment with the antiandrogenic PAHs. 5. While xenobiotic responsive element (AhR-binding sequence) exists in the promoter/enhancer regions of androgen-regulated genes, xenobiotic response element is not important. These results demonstrate that AhR activated by PAH forms a complex with AR and consequently inhibits the function of AR as a transcription factor, leading to the antiandrogenic activities of PAHs. Next, the cross-talk between AhR and AR was studied in androgen responsive cell lines. The results obtained are as follows. 6. 5α-Dihydrotestosterone (DHT), an androgen, elevated the mRNA level of CYP1A1 gene, an AhR-regulated gene and this effect was concentration-dependent. 7. R1881, a synthetic androgen with agonist activity, has a similar activity. 8. DHT does not show the effect in the cell that AR is knocked-down by siRNA for AR. 9. DHT shows no activity in the reporter assay system in which expression of reporter gene is dependent upon only AR responsive element. These results indicate that there exists the cross-talk between AhR and AR signal transduction pathways.
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