Higa Arisa, Hoshi Hirotaka, Yanagisawa Yuka, Ito Emi, Morisawa Gaku, Imai Jun-Ichi, Watanabe Shinya, Takagi Motoki
Medical-Industrial Translational Research Center, Fukushima Medical University.
J Toxicol Sci. 2017;42(6):755-761. doi: 10.2131/jts.42.755.
In recent years, human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been widely used to develop evaluation systems for drug cardiotoxicity, including the arrhythmia caused by QT prolongation. To accurately assess the arrhythmogenic potential of drugs, associated with QT prolongation, we developed an evaluation system using hiPS-CMs and gene expression analysis. hiPS-CMs were treated with 8 arrhythmogenic and 17 non-arrhythmogenic drugs at several concentrations for 24 hr to comprehensively analyze gene expression. The results showed that 19 genes were upregulated in the arrhythmogenic drug-treated cells compared with their expression levels in the non-treated and non-arrhythmogenic drug-treated cells. The arrhythmogenic risks of the drugs were evaluated by scoring gene expression levels. The results indicated that arrhythmogenic risks could be inferred when cells were treated at a concentration 100 times higher than the maximum blood concentration of the drug. Thus, we succeeded in developing a system for evaluation of the arrhythmogenic potential of drugs using gene expression analysis.
近年来，人诱导多能干细胞衍生的心肌细胞（hiPS-CMs）已被广泛用于开发药物心脏毒性评估系统，包括由QT延长引起的心律失常。为了准确评估与QT延长相关的药物致心律失常潜力，我们利用hiPS-CMs和基因表达分析开发了一种评估系统。用8种致心律失常药物和17种非致心律失常药物在几个浓度下处理hiPS-CMs 24小时，以全面分析基因表达。结果显示，与未处理和非致心律失常药物处理的细胞相比，致心律失常药物处理的细胞中有19个基因上调。通过对基因表达水平进行评分来评估药物的致心律失常风险。结果表明，当细胞在高于药物最大血药浓度100倍的浓度下处理时，可以推断有致心律失常风险。因此，我们成功开发了一种利用基因表达分析评估药物致心律失常潜力的系统。
