Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver
Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver
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DOI：
10.2131/jts.42.589
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发表时间：
2017-10-01
影响因子：
2
通讯作者：
Ohta, Shigeru
中科院分区：
文献类型：
--
作者：
Sanoh, Seigo;Yamachika, Yuto;Ohta, Shigeru
重要的是要考虑动物和人类之间对药物诱导毒性的敏感性。具有人源化肝脏的嵌合小鼠预期可预测人类的肝毒性。药物诱导的磷脂病（DIPL），其中磷脂积累，是一个已知的实体。在这项研究中，我们研究了嵌合小鼠是否可以揭示DIPL的物种差异。研究了胺碘酮诱导磷脂病后嵌合小鼠肝脏中各种磷脂酰胆碱（PhC）分子的变化。液相色谱-串联质谱法显示，胺碘酮给药后肝脏中的PhCs水平趋于增加。嵌合小鼠的肝脏由人肝细胞和残余小鼠肝细胞组成。我们使用成像质谱（IMS）来评估胺碘酮给药后人和小鼠肝细胞中PhCs的增加。IMS可视化组织中内源性和外源性分子的定位。IMS分析表明，人肝细胞中几种PhC的局部水平往往高于小鼠肝细胞中的水平，PhC水平因胺碘酮而发生变化。具有人源化肝脏的嵌合小鼠将用于评估小鼠和人之间DIPL的物种差异。
It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Drug induced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity. In this study, we examined whether chimeric mice can reveal species differences in DIPL. Changes in various phosphatidylcholine (PhC) molecules were investigated in the liver of chimeric mice after administering amiodarone, which induces phospholipidosis. Liquid chromatography-tandem mass spectrometry revealed that levels of PhCs tended to increase in the liver after administration of amiodarone. The liver of chimeric mice consists of human hepatocytes and residual mouse hepatocytes. We used imaging mass spectrometry (IMS) to evaluate the increase of PhCs in human and mouse hepatocytes after administration of amiodarone. IMS visualizes localization of endogenous and exogenous molecules in tissues. The IMS analysis suggested that the localized levels of several PhCs tended to be higher in the human hepatocytes than those in mouse hepatocytes, and PhC levels changed in response to amiodarone. Chimeric mice with a humanized liver will be useful to evaluate species differences in DIPL between mice and humans.