Ibrahim Mohamed A, Abdel-Aziz Asmaa, El-Sheikh Azza, Kamel Maha, Khalil Al-Zahraa, Abdelhaleem Hisham
Faculty of Medicine, Minia University, Egypt.
Clin Exp Hepatol. 2018 Sep;4(3):175-181. doi: 10.5114/ceh.2018.78121. Epub 2018 Sep 10.
The study aimed at investigating the hepatic effect of direct acting anti-hepatitis C virus drugs (DAAs), sofosbuvir (Sof) and daclatasvir (Dac), in thioacetamide (TAA)-induced liver injury in rats.
Animals were allocated to 7 groups: a normal control group, a TAA group (receiving TAA 50 mg/kg, i.p. twice weekly), two TAA groups receiving either a low or a high dose of Sof (Sof-L and Sof-H; 41.1 mg/kg and 82.2 mg/kg, respectively), two TAA groups receiving either a low or a high dose of Dac (Dac-L and Dac-H; 6.2 mg/kg and 12.4 mg/kg, respectively), and a TAA group receiving both Sof-L and Dac-L.
After 6 weeks, TAA significantly elevated the serum activities of liver enzymes, along with histopathological evidence of liver injury. These findings were associated with a significant increase in a fibrotic marker (tissue inhibitor metalloproteinase-1 - TIMP-1), proinflammatory cytokine (tumor necrosis factor alpha - TNF-α), and oxidative stress parameters (malondialdehyde [MDA] content, and superoxide dismutase [SOD] and catalase activities) in hepatic tissue. TAA rats treated with Sof-L, Dac-L, Dac-H and a combination of Sof-L plus Dac-L showed significant amelioration of TAA-induced liver injury. Their effects were accompanied by a significant reduction in TIMP-1, TNF-α and oxidative stress parameters in hepatic tissue. Interestingly, Sof-H caused no improvement in TAA-induced hepatic injury.
The hepatic effects of Sof and Dac in TAA-induced liver injury appeared to be mediated by anti-oxidant effects, and inhibition of TNF-α and TIMP-1.
本研究旨在调查直接作用的抗丙型肝炎病毒药物（DAAs）索磷布韦（Sof）和达卡他韦（Dac）对硫代乙酰胺（TAA）诱导的大鼠肝损伤的肝脏影响。
将动物分为7组：正常对照组、TAA组（每周两次腹腔注射50 mg/kg TAA）、两个分别接受低剂量或高剂量Sof的TAA组（Sof-L和Sof-H；分别为41.1 mg/kg和82.2 mg/kg）、两个分别接受低剂量或高剂量Dac的TAA组（Dac-L和Dac-H；分别为6.2 mg/kg和12.4 mg/kg），以及一个同时接受Sof-L和Dac-L的TAA组。
6周后，TAA显著提高了血清肝酶活性，并伴有肝损伤的组织病理学证据。这些发现与肝组织中纤维化标志物（组织金属蛋白酶抑制剂-1 - TIMP-1）、促炎细胞因子（肿瘤坏死因子-α - TNF-α）以及氧化应激参数（丙二醛[MDA]含量、超氧化物歧化酶[SOD]和过氧化氢酶活性）的显著增加有关。用Sof-L、Dac-L、Dac-H以及Sof-L加Dac-L联合治疗的TAA大鼠显示TAA诱导的肝损伤有显著改善。它们的作用伴随着肝组织中TIMP-1、TNF-α和氧化应激参数的显著降低。有趣的是，Sof-H并未改善TAA诱导的肝损伤。
Sof和Dac对TAA诱导的肝损伤的肝脏影响似乎是由抗氧化作用以及对TNF-α和TIMP-1的抑制介导的。
