Mechanism for human-specific hepatotoxicity and development of prediction system
| Project/Area Number |
17390039
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Tohoku University |
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Principal Investigator |
YAMAZOE Yasushi Tohoku University Grad. Sch. Pharm.Sci., Professor, 大学院薬学研究科, 教授 (00112699)
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| Co-Investigator(Kenkyū-buntansha) |
MIYATA Masaaki Tohoku University Grad. Sch. Pharm.Sci., Reserch Instructor, 大学院薬学研究科, 助手 (90239418)
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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 |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2006: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2005: ¥11,100,000 (Direct Cost: ¥11,100,000)
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| Keywords | flutamide / hepatotoxicity / Sult2a / lithocholic acid / CYP3A4 / ampicillin / cholic acid / TCPOBOP / モデル動物 / 毒性機序 |
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| Research Abstract |
To identify the mechanism for human-specific hepatotoxicity and develop the prediction system, flutamide and bile acid models were used. The metabolism of flutamide was analyzed using human CYP expressed microsomes. FLU-1-N-OH (N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine) which is a candidate of metabolic intermediate for flutamide-induced hepatotoxicity was produced from FLU-1 by human CYP3A4. In mice, FLU-1 N-hydroxylation was mainly catalyzed by Cyp isoforms different from Cyp3a isoforms. Furthermore, mouse hepatotoxicity model was established by co-treatment with FLU-1 and TCPOBOP. We are analyzing the mechanism for fulutamide-induced hepatotoxicity using the mouse model.
To analyze the mechamism for hepatotoxicity through the interaction between endogenous compound (bile acid) and drug, C57/BL6 male mice were treated with cholic acid and ampicillin. Cholic acid (CA) or ampicillin treatment did not cause hepatotoxicity, but CA and ampicillin co-treatment cause severe hepatotoxicity in the mice. These results suggest the presence of the interaction between CA and ampicilin involved in hepatotoxicity. On the other hand, cholic acid treatment causes hepatotoxicity in fornesoid X receptor (FXR)-null mice. After co-treatment with 1.25% cholesterol (Chol), serum ALT and ALP activities were significantly decreased in FXR-null mice fed a 0.5% cholic acid diet, as compared to those of the CA diet controls. Clear decreases were observed on ileal bile acid absorption capacity estimated by a in situ loop method and contents of ileal Asbt protein in FXR-null mice fed the CA plus Chol diet. These results indicate a protective role of cholesterol against bile acid-induced toxicity and also suggest the presence of an FXR-independent suppressive mechanism of ileal bile acid absorption.
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Report
(3 results)
Research Products
(9 results)
