Davis Madison, Stamper Brendan D
Pacific University School of Pharmacy, 222 SE 8th Avenue No. 451, Hillsboro, OR 97123, USA.
Biomed Res Int. 2016;2016:4780872. doi: 10.1155/2016/4780872. Epub 2016 Dec 15.
In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor- transgenic mouse hepatocyte (TAMH) cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK). The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP), tetrafluoroethylcysteine (TFEC), flutamide, PD0325901, lapatinib, and flupirtine.
肝毒性的体外模型可作为预测体内反应的有用工具。在本综述中，我们讨论了转化生长因子转基因小鼠肝细胞（TAMH）细胞系的应用，该细胞系因其能够保持稳定表型并表达药物代谢酶，是研究药物性肝损伤的一个有吸引力的模型。肝毒性涉及肝脏损伤，且常与化学物质暴露相关。由于肝脏是药物代谢的主要场所，药物性肝损伤是某些药物严重的健康问题。在分子水平上，在药物诱导的肝细胞损伤过程中，各种机制可能保护或损害肝脏，包括信号通路和内源性因子（如Bcl-2、谷胱甘肽、Nrf2或丝裂原活化蛋白激酶）。药物或药物代谢物暴露后，肝细胞中这些通路与其他通路之间的相互作用会发生变化，导致细胞内应激，最终导致细胞死亡和肝损伤。本综述重点关注在TAMH细胞系中研究药物诱导毒性的机制研究，以及该模型中肝毒性机制的改变与体内情况的关系。本文讨论的药物包括对乙酰氨基酚（APAP）、四氟乙基半胱氨酸（TFEC）、氟他胺、PD0325901、拉帕替尼和氟吡汀。
