Establishment of drug hypersensitivity animal model and investigation of the mechanism.

药物过敏动物模型的建立及机制研究。

• 批准号: 24659073
• 负责人: YOKOI Tsuyoshi
• 金额: $ 2.5万
• 依托单位: Nagoya University (2013)Kanazawa University (2012)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24659073/
• 关键词: 医薬品副作用; 薬物相互作用; hypersensitivity; 皮膚障害; 薬物性肝障害; フェニトイン; カルバマゼピン; バイオマーカー; 薬物過敏症; 薬物アレルギー; 免疫学的因子; 反応性代謝物; 代謝的活性化

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are major causes to attrition during clinical studies. Formation of reactive metabolites of drugs by drug-metabolizing enzymes has been focused. Considering the species differences and interindividual differences, studies for developing the prediction method of SJS/TEN in non-clinical drug development were conducted. However, SJS/TEN with very low incidence are hard to predict, because the immune- and inflammatory-related factors were not able be considered. Recently, we have established animal models of drug-induced liver injury in 10 kinds of clinical drugs. However, the phenotypic consequence of SJS/TEN in mouse model showed very low reproducibility, even with many difference experimental conditions. Thus, we clarified the mechanism of hepatic inflammation by carbamazepine and phenytoin (representative drugs for SJS/TEN) in mouse.

史蒂文斯-约翰逊综合征 (SJS) 和中毒性表皮坏死松解症 (TEN) 是临床研究期间人员流失的主要原因。通过药物代谢酶形成药物反应性代谢物已成为人们关注的焦点。考虑物种差异和个体差异，开展非临床药物开发中SJS/TEN预测方法的研究。然而，发生率很低的SJS/TEN很难预测，因为无法考虑免疫和炎症相关因素。近期我们建立了10种临床药物引起的药物性肝损伤动物模型。然而，即使在许多不同的实验条件下，SJS/TEN 在小鼠模型中的表型结果显示出非常低的重现性。由此，我们阐明了卡马西平和苯妥英（SJS/TEN的代表药物）引起小鼠肝脏炎症的机制。

项目成果

A novel mouse model for phenytoin-induced liver injury: involvement of immune-related factors and P450-mediated metabolism.

• DOI: 10.1093/toxsci/kft184
• 发表时间: 2013-11
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: E. Sasaki;K. Matsuo;A. Iida;K. Tsuneyama;T. Fukami;M. Nakajima;T. Yokoi

体内動態と薬物相互作用の基礎と応用-食品成分への展開-

药代动力学和药物相互作用的基础和应用 - 在食品成分中的应用 -

• 发表时间: 2013
• 期刊: 食品加工技術
• 作者: Eita Sasaki;Kentaro Matsuo;Azumi Iida;Koichi Tsuneyama;Tatsuki Fukami;Miki Nakajima;and Tsuyoshi Yokoi;横井毅
• 通讯作者: 横井毅

Identification of a P450-mediated hepatotoxicity-associated glutathione-conjugate of phenytoin in phenytoin-induced liver injury in mice

苯妥英诱导的小鼠肝损伤中 P450 介导的肝毒性相关苯妥英谷胱甘肽缀合物的鉴定

• 发表时间: 2014
• 作者: Tsuyoshi Yokoi;Eita Sasaki;Atsushi Iwamura;Tatsuki Fukami;Miki Nakajima;Toshiyuki Kume
• 通讯作者: Toshiyuki Kume

毒作用発現バイオマーカーとしてのマイクロRNA

MicroRNA 作为毒性表达生物标志物

• 发表时间: 2012
• 作者: 樋口悟法;常山幸一;深見達基;中島美紀;横井毅;横井 毅;横井 毅;横井 毅
• 通讯作者: 横井 毅

薬物性肝障害における免疫・炎症因子の関与

免疫和炎症因子在药物性肝损伤中的作用

• 发表时间: 2014
• 期刊: 日本皮膚アレルギー・接触皮膚炎学会雑誌
• 作者: 織田進吾;横井毅
• 通讯作者: 横井毅