| Project/Area Number |
15390172
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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 |
Applied pharmacology
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| Research Institution | Kanazawa University |
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Principal Investigator |
YOKOI Tsuyoshi Kanazawa University, Division of Pharmaceutical Sciences, Professor, 医学系研究科, 教授 (70135226)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Miki Kanazawa University, Division of Pharmaceutical Sciences, Associate Professor, 医学系研究科, 助教授 (70266162)
KATOH Miki Kanazawa University, Division of Pharmaceutical Sciences, Research Associate, 自然科学研究科, 助手 (70345594)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2005: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2004: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2003: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | troglitazone / DNA microarray / drug induced hepatotoxicity / prediction / QT clastering / acetaminophen / QTクラスタリング / 四塩化炭素 / アルドラーゼB / 自己抗体 / 肝毒性 / ラット / クラスタリング解析 / DNAチップ / ジエチルニトロソアミン |
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| Research Abstract |
We investigated whether there is relationship in gene expression profiles of hepatotoxic chemicals administration by using Rat Drug Response Chip. Liver mRNA was isolated from the typical hepatotoxicant-administered rats and performed DMA microarray containing 1,097 drug response genes. All the tested chemicals generated a specific gene expression patterns. APAP was sorted different cluster from other chemicals. From serum biochemical markers profiles, we identified up-regulated 10 genes and down-regulated 10 genes as a potential marker of hepatotoxicity. By using QT clustering, we identified major up-regulated and down-regulated expression patterns from each chemical. Interestingly, these means of expression patterns had good correlation with expression patterns from biochemical markers profiles. In conclusion, we identified 20 potential toxicity markers and expression profile analysis of chemicals administration can guess toxic time point with independent of toxicity level and using
… More
this expression profile analysis was also available to be one of the tools of detecting potential hepatotoxicant.
We used typical hepatotoxicant thioacetamide (TA), constructed liver toxicity model rats to perform simultaneous measurement of gene expression profiles and to find correlation between dosage and time. Serum AST and ALT were increased by TA administration with dose dependent manner and reached the maximal value at 24 hours. Hierarchical clustering analysis of all dosage groups showed 2 major clusters. Moreover, hierarchical clustering analysis of each dosage group showed the same pattern as shown in all dosage groups. Furthermore, gene expression majority obtained by QT clustering analysis had the same maximal time point of TA toxicity. Individual gene expression profiles selected our previous studies were independent on their dosage. These finding suggest that potential toxic effects in the absense of the occurrence of toxicity are independent on their dosage, and following specific gene expression profiles and general gene expression profiles can be a sensitive marker of toxicity. Less
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