Hirashima Rika, Itoh Tomoo, Tukey Robert H, Fujiwara Ryoichi
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
Drug-induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI-associated genes such as S100 calcium-binding protein A and interleukin (IL)-1β are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI-associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL-1β basal expression. They also showed a higher inducibility of IL-1β when treated by pioglitazone. Mice at higher risk for DILI showed even higher sums of DILI-associated gene basal expression levels and induction rates in keratinocytes. Our data suggest that DILI-associated genes might be involved in the onset and progression of drug-induced skin toxicity. Furthermore, we might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes. Copyright © 2017 John Wiley & Sons, Ltd.
药物性肝损伤（DILI）是最常见的药物不良反应之一。DILI常伴有皮肤反应，包括皮疹和瘙痒。然而，尚不清楚诸如S100钙结合蛋白A和白细胞介素（IL）-1β等与DILI相关的基因是否参与药物诱导的皮肤毒性反应。在本研究中，大多数受试肝毒性药物，如吡格列酮和双氯芬酸，可在人和小鼠角质形成细胞中诱导与DILI相关的基因。具有较高DILI风险的小鼠角质形成细胞表现出IL-1β基础表达增加。当用吡格列酮处理时，它们还表现出更高的IL-1β诱导性。具有较高DILI风险的小鼠在角质形成细胞中显示出更高的与DILI相关基因基础表达水平总和及诱导率。我们的数据表明，与DILI相关的基因可能参与药物诱导的皮肤毒性反应的发生和发展。此外，通过检查角质形成细胞中的基因表达模式，我们或许能够以侵入性较小的方式识别出发生DILI风险较高的个体。版权所有© 2017约翰威立父子有限公司。
