2012 Fiscal Year Final Research Report
Quantitative analysis of drugs induced BSEP inhibition and cholestatic hepatotoxicity
| Project/Area Number |
23659073
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Chiba University |
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Principal Investigator |
HORIE Toshiharu 千葉大学, 大学院・薬学研究院, 教授 (90120154)
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| Co-Investigator(Kenkyū-buntansha) |
SHITARA Yoshihisa 千葉大学, 大学院・薬学研究院, 准教授 (00306656)
SEKINE Shuichi 千葉大学, 大学院・薬学研究院・, 助教 (70401007)
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| Project Period (FY) |
2011 – 2012
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| Keywords | 薬物動態 / 代謝学 |
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| Research Abstract |
Drug-induced liver injury (DILI) is a major reason for the dropout of candidate compounds from drug testing and the withdrawal of pharmaceuticals from clinical use. Among the various mechanisms of liver injury, the accumulation of bile acids (BAs) within hepatocytes is thought to be a primary mechanism for the development of DILI. Although bile salt export pump (BSEP) dysfunction is considered a susceptibility factor for DILI, little is known about the relationship between drug-induced BSEP dysfunction and BA-dependent hepatotoxicity. Furthermore, few methods are at hand for the systematic and quantitative evaluation of BA-dependent DILI. This study aimed to construct a model of DILI by employing sandwich-cultured hepatocytes (SCHs). SCHs can be used to assess functions of canalicular transporters such as BSEP and the activity of metabolic enzymes. Here, the impact of 25 test compounds was investigated on BA-dependent cytotoxicity in SCHs. As a result, BA-dependent toxicity was observed for 11 test compounds in SCHs treated in the presence of BAs, while no signs of toxicity were observed for SCHs treated in the absence of BAs. Of the 11 compounds, nine were known BSEP inhibitors. Moreover, for some compounds, an increase in the severity of BA-dependent toxicity was observed in SCHs that were co-treated with 1-aminobenzotriazole, a non-selective inhibitor of cytochrome P450 (CYP450)-mediated drug metabolism. These results indicate that the SCH-based model is likely to prove useful for the evaluation of BA-dependent DILI, including the effects of drug metabolism and BSEP inhibition on liver injury.
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Research Products
(44 results)
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[Presentation] C型肝炎ウイルスコア蛋白質と鉄により誘発される細胞障害増悪に対するミトコンドリア鉄取り込み機構の関与2012
Author(s)
伊藤好美,関根秀一,堀江利治,小池和彦,森屋恭爾,新谷良澄,藤江肇,堤武也,三好秀征,藤永秀剛,新澤靖子, 藤江肇,堤武也,三好秀征,藤永秀剛,新澤 靖子
Organizer
第132年会 日本薬学会
Place of Presentation
札幌
Year and Date
20120328-31
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[Presentation] C型肝炎の病態悪化に対するミトコンドリア鉄蓄積と鉄取り込み機構の関与2012
Author(s)
伊藤好美,関根秀一,堀江利治,小池和彦,森屋恭爾,新谷良澄,藤江肇,堤武也,三好秀征,藤永秀剛,新澤靖子, 藤江肇,堤武也,三好秀征,藤永秀剛,新澤 靖子
Organizer
肝病態生理研究会
Place of Presentation
金沢
Year and Date
2012-06-06
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[Presentation] C型肝炎ウイルスコア蛋白質により誘発されるミトコンドリア障害に対する鉄蓄積の関与2011
Author(s)
伊藤好美,関根秀一,堀江利治,小池和彦,森屋恭爾,新谷良澄,藤江肇,堤武也,三好秀征,藤永秀剛,新澤靖子, 藤江肇,堤武也,三好秀征,藤永秀剛,新澤 靖子
Organizer
第131年会 日本薬学会
Place of Presentation
静岡
Year and Date
20110328-31
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