Tang Nan, Cai Ziqing, Chen Hongpeng, Cao Longbin, Chen Bo, Lin Bihua
School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China.
School of Information Engineering, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China.
Exp Ther Med. 2019 Apr;17(4):2799-2806. doi: 10.3892/etm.2019.7244. Epub 2019 Feb 6.
Gap junctions (GJs), which are important plasma membrane channels for the transfer of signaling molecules between adjacent cells, have been implicated in drug-induced liver injury. However, the influence and the underlying mechanisms of GJs in propylthiouracil (PTU)-induced hepatotoxicity are unclear. In the present study, distinct manipulations were performed to regulate GJ function in the BRL-3A rat liver cell line. The results indicated that the toxic effect of PTU in BRL-3A cells was mediated by GJ intercellular communication, as cell death was significantly attenuated in the absence of functional GJ channels. Furthermore, the specific knockdown of connexin-32 (Cx32; a major GJ component protein in hepatocytes) using small interfering RNA was observed to decrease necrosis, intracellular PTU content and the level of reactive oxygen species (ROS) following PTU exposure. These observations demonstrated that suppressing GJ Cx32 could confer protection against PTU-induced cytotoxicity through decreasing the accumulation of PTU and ROS. To the best of our knowledge, the present study is the first to demonstrate the role and possible underlying mechanisms of GJs in the regulation of PTU-induced toxicity in BRL-3A rat liver cells.
间隙连接（GJs）是相邻细胞间传递信号分子的重要质膜通道，与药物性肝损伤有关。然而，间隙连接在丙硫氧嘧啶（PTU）诱导的肝毒性中的影响及潜在机制尚不清楚。在本研究中，我们进行了不同的操作来调节BRL-3A大鼠肝细胞系中的间隙连接功能。结果表明，PTU对BRL-3A细胞的毒性作用是由间隙连接的细胞间通讯介导的，因为在没有功能性间隙连接通道的情况下，细胞死亡明显减轻。此外，使用小干扰RNA特异性敲低连接蛋白32（Cx32；肝细胞中主要的间隙连接组成蛋白）后，观察到PTU暴露后坏死、细胞内PTU含量和活性氧（ROS）水平降低。这些观察结果表明，抑制间隙连接Cx32可通过减少PTU和ROS的积累来保护细胞免受PTU诱导的细胞毒性。据我们所知，本研究首次证明了间隙连接在调节PTU诱导的BRL-3A大鼠肝细胞毒性中的作用及可能的潜在机制。
