Yousefsani Bahare Sadat, Nabavi Nasim, Pourahmad Jalal
Research Institute for Islamic and Complementary Medicine, Iran University of Medical Sciences, Tehran, Iran.
School of Persian Medicine, Iran University of Medical Sciences, Tehran, Iran.
Drug Res (Stuttg). 2020 Apr;70(4):137-144. doi: 10.1055/a-1117-3004. Epub 2020 Mar 10.
Sofosbuvir, the oral direct-acting antiviral, is a medication, which used as the effective treatment for hepatitis C infection. Although sofosbuvir thought to have few adverse-effects, there have been some experiences of serious drug-induced hepatotoxicity. In this research, the molecular/cellular pathways that lead to sofosbuvir-induced hepatotoxicity were evaluated on isolated rat hepatocytes. Rat hepatocytes were isolated using collagenase reperfusion technique. In evaluating the different pathways of sofosbuvir-induced hepatotoxicity, ROS formation, mitochondrial membrane potential collapse, lysosomal membrane damage, glutathione depletion, and the percentage of apoptosis versus necrosis were determined. Our data demonstrated that the cytotoxic effect of sofosbuvir in lower concentrations (25, 50 and 100 µM) is mediated by above stream pathways. On the other hand, sofosbuvir acts in opposite directions at higher concentrations (400 µM) and acts as an antioxidant and hepatoprotective. We concluded that sofosbuvir while looking toxic and pro-oxidant in lower concentrations, acts as protective and antioxidant in higher concentrations.
索磷布韦是一种口服直接作用抗病毒药物，用于有效治疗丙型肝炎感染。尽管索磷布韦被认为不良反应较少，但仍有一些严重药物性肝毒性的案例。在本研究中，我们在分离的大鼠肝细胞上评估了导致索磷布韦诱导肝毒性的分子/细胞途径。采用胶原酶再灌注技术分离大鼠肝细胞。在评估索磷布韦诱导肝毒性的不同途径时，测定了活性氧生成、线粒体膜电位崩溃、溶酶体膜损伤、谷胱甘肽耗竭以及凋亡与坏死的百分比。我们的数据表明，较低浓度（25、50和100µM）的索磷布韦的细胞毒性作用是由上游途径介导的。另一方面，索磷布韦在较高浓度（400µM）时作用方向相反，起到抗氧化剂和肝脏保护剂的作用。我们得出结论，索磷布韦在较低浓度下看似有毒且具有促氧化作用，但在较高浓度下则起到保护和抗氧化作用。
