Understanding the fundamental mechanisms that govern the fate of cells during drug-induced intrahepatic cholestasis provides strategies for the establishment of evaluation methods for drug screening. In the present study, the aggregates of a differentiated human hepatic cell line, HepaRG, were incubated in medium with Y27632 or bosentan to clarify the changes in the behavior of bile canaliculi (BC) with the growth of cells during drug-induced intrahepatic cholestasis. With elapsed exposure time, the aggregates in the culture with bosentan caused the dilation of BC, and the hepatocytes ultimately exhibited apoptotic death after the disruption of BC. Y27632 caused the disruption of BC in the aggregates after dilation. However, there was no change in the number of cells within the aggregates in the culture with Y27632, in spite of its cytotoxicity. After 144 h from the start of Y27632 exposure, the aggregates showed the rearrangement of BC. To inhibit cell division, the aggregates exposed to Y27632, which exhibited disruption of BC, were treated with mitomycin C for 2 h and continuously exposed to Y27632. The inhibition of cell division could not induce the rearrangement of BC within these aggregates, which was similar to the phenomenon observed in the aggregates exposed to bosentan. These findings indicate that growth is an important factor that influences the switching of cell fate toward survival or death in drug-induced intrahepatic cholestasis process. Thus, the autoregulation of growth is a major contributor to the rearrangement of BC within aggregates.

理解在药物诱导的肝内胆汁淤积过程中控制细胞命运的基本机制，为建立药物筛选评估方法提供了策略。在本研究中，将分化的人类肝细胞系HepaRG的聚集体与Y27632或波生坦一起在培养基中孵育，以阐明药物诱导的肝内胆汁淤积过程中胆管（BC）行为随细胞生长的变化。随着暴露时间的流逝，波生坦培养物中的聚集体引起BC的膨胀，并且在BC破坏后，肝细胞最终表现出凋亡性死亡。Y27632导致膨胀后骨料中的BC破坏。但是，尽管具有细胞毒性，但在用Y27632培养的细胞中，聚集物中的细胞数量没有变化。从暴露Y27632开始144小时后，聚集体显示BC重排。为了抑制细胞分裂，将暴露于表现出BC破坏的Y27632的聚集体用丝裂霉素C处理2 h，然后连续暴露于Y27632。细胞分裂的抑制不能诱导这些聚集体中BC的重排，这类似于在暴露于波生坦的聚集体中观察到的现象。这些发现表明，在药物诱导的肝内胆汁淤积过程中，生长是影响细胞命运向存活或死亡转换的重要因素。因此，生长的自动调节是骨料中BC重排的主要因素。将暴露于Y27632且表现出BC破坏的聚集体用丝裂霉素C处理2 h，然后连续暴露于Y27632。细胞分裂的抑制不能诱导这些聚集体中BC的重排，这类似于在暴露于波生坦的聚集体中观察到的现象。这些发现表明，在药物诱导的肝内胆汁淤积过程中，生长是影响细胞命运向存活或死亡转换的重要因素。因此，生长的自动调节是骨料中BC重排的主要因素。暴露于Y27632且表现出BC破坏的聚集体用丝裂霉素C处理2 h，然后连续暴露于Y27632。细胞分裂的抑制不能诱导这些聚集体中BC的重排，这类似于在暴露于波生坦的聚集体中观察到的现象。这些发现表明，在药物诱导的肝内胆汁淤积过程中，生长是影响细胞命运向存活或死亡转换的重要因素。因此，生长的自动调节是骨料中BC重排的主要因素。这与暴露于波生坦的聚集体中观察到的现象相似。这些发现表明，在药物诱导的肝内胆汁淤积过程中，生长是影响细胞命运向存活或死亡转换的重要因素。因此，生长的自动调节是骨料中BC重排的主要因素。这与暴露于波生坦的聚集体中观察到的现象相似。这些发现表明，生长是影响药物诱导的肝内胆汁淤积过程中细胞命运向存活或死亡转换的重要因素。因此，生长的自动调节是骨料中BC重排的主要因素。