Zhang Huijie, He Zhixin, Deng Ping, Lu Muxue, Zhou Chao, Yang Lingling, Yu Zhengping
Medical College, Guangxi University, 100 University East Road, Xixiangtang District, Nanning, Guangxi, 530004, P. R. China.
Department of Occupational Health, Third Military Medical University, 30 Gaotanyan Zhengjie, Shapingba District, Chongqing, 400038, P. R. China.
Toxicol Res (Camb). 2022 Jul 8;11(4):628-643. doi: 10.1093/toxres/tfac040. eCollection 2022 Aug.
Arsenic, a widely existing environmental contaminant, is recognized to be toxic to multiple organs. Exposure to arsenic results in liver damage via excessive production of reactive oxidative species (ROS). PIN1 regulates the levels of ROS. N-acetyl-L-cysteine (NAC) is an ROS scavenger that protects the hepatic functions. Whether PIN1 plays a regulatory role in NAC-mediated antagonism against arsenic hepatotoxicity remains largely unknown. In our study, the protective effects of NAC against arsenic (NaAsO)-induced hepatotoxicity were evaluated in vitro and in vivo. Arsenic exposure induced cytotoxicity by increasing the intracellular ROS production, impairing mitochondrial function and inducing apoptosis in L02 hepatocytes. Overexpression of PIN1 markedly protected against arsenic cytotoxicity, decreased ROS levels, and mitigated mitochondrial dysfunction and apoptosis in L02 cells. However, loss of PIN1 further aggravated arsenic-induced cytotoxicity and abolished the protective effects of NAC in L02 cells. An in vivo study showed that pretreatment with NAC rescued arsenic-induced liver injury by restoring liver function and suppressing hepatic oxidative stress. Overexpression of PIN1 in mice transfected with AAV- relieved arsenic-induced liver dysfunction and hepatic oxidative stress. Taken together, our study identified PIN1 as a novel intervention target for antagonizing arsenic-induced hepatotoxicity, highlighting a new pharmacological mechanism of NAC targeting PIN1 in antagonism against arsenic toxicity.
砷是一种广泛存在的环境污染物，被认为对多个器官有毒性。接触砷会通过过量产生活性氧化物质（ROS）导致肝脏损伤。PIN1调节ROS水平。N-乙酰-L-半胱氨酸（NAC）是一种ROS清除剂，可保护肝功能。PIN1是否在NAC介导的对抗砷肝毒性中发挥调节作用在很大程度上仍不清楚。在我们的研究中，在体外和体内评估了NAC对砷（NaAsO）诱导的肝毒性的保护作用。砷暴露通过增加细胞内ROS产生、损害线粒体功能和诱导L02肝细胞凋亡来诱导细胞毒性。PIN1的过表达显著保护细胞免受砷细胞毒性，降低ROS水平，并减轻L02细胞中的线粒体功能障碍和凋亡。然而，PIN1的缺失进一步加重了砷诱导的细胞毒性，并消除了NAC在L02细胞中的保护作用。一项体内研究表明，NAC预处理通过恢复肝功能和抑制肝脏氧化应激来挽救砷诱导的肝损伤。用腺相关病毒（AAV）转染的小鼠中PIN1的过表达减轻了砷诱导的肝功能障碍和肝脏氧化应激。综上所述，我们的研究确定PIN1是对抗砷诱导的肝毒性的新干预靶点，突出了NAC靶向PIN1对抗砷毒性的新药理机制。
