Wang Shan, Tian Yu, Lu Shan, Wang Ruiying, Shang Hai, Zhang Xuelian, Zhang Chenyang, Sun Guibo, Xu Xudong, Sun Xiaobo
Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.
RSC Adv. 2019 May 15;9(27):15224-15228. doi: 10.1039/c9ra00483a. eCollection 2019 May 14.
Drug-induced liver injury is one of the main causes of drug non-approval and drug withdrawal by the Food and Drug Administration (FDA). Acetaminophen (APAP) is a widely used non-steroidal anti-inflammatory drug for treating fever and headache. APAP is considered safe at therapeutic doses; however, there have been reports of acute liver injury following the administration of APAP. To explore APAP hepatotoxicity and its mechanisms, we designed and synthesized a new click chemistry probe, APAP-P1, in our current study. We introduced the PEG-azide probe linker into the acetyl group of acetaminophen. First, we evaluated the probe toxicity in HepaRG cells and found that it still retained hepatotoxicity. We also found that this probe APAP-P1 can be metabolized by HepaRG cells. This demonstrated that the APAP-P1 probe still kept its metabolism characteristics. Using this probe, we pulled down its potential targets and . APAP can directly target TrxR1; thus, we tested for this interaction by Western blotting of pull-down proteins. The results showed that APAP-P1 can pull down TrxR1 and .
药物性肝损伤是药物未获美国食品药品监督管理局（FDA）批准及撤市的主要原因之一。对乙酰氨基酚（APAP）是一种广泛用于治疗发热和头痛的非甾体抗炎药。治疗剂量下的APAP被认为是安全的；然而，已有服用APAP后出现急性肝损伤的报道。为探究APAP的肝毒性及其机制，我们在当前研究中设计并合成了一种新型点击化学探针APAP-P1。我们将聚乙二醇-叠氮化物探针连接体引入对乙酰氨基酚的乙酰基中。首先，我们评估了该探针在HepaRG细胞中的毒性，发现它仍保留肝毒性。我们还发现该探针APAP-P1可被HepaRG细胞代谢。这表明APAP-P1探针仍保持其代谢特性。使用该探针，我们下拉了其潜在靶点 以及 。APAP可直接靶向硫氧还蛋白还原酶1（TrxR1）；因此，我们通过对下拉蛋白进行蛋白质印迹法检测这种相互作用。结果表明APAP-P1可下拉TrxR1 以及 。
