Alanazi Ahmed Z, Alhazzani Khalid, Alrewily Salah Q, Aljerian Khaldoon, Algahtani Mohammad M, Alqahtani Qamraa H, Haspula Dhanush, Alhamed Abdullah S, Alqinyah Mohammed, Raish Mohammad
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 12372, Saudi Arabia.
Department of Pathology, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia.
Pharmaceuticals (Basel). 2023 Jun 23;16(7):921. doi: 10.3390/ph16070921.
Dasatinib (DASA) is a novel tyrosine kinase inhibitor, approved for leukemia treatment. However, the long-term use of DASA induces several complications, especially liver damage. On the other hand, Naringenin (NGN) is a potent antioxidant and anti-inflammatory agent which is known to exert protective effects in several liver disease animal models. Yet, the effect of NGN on DASA-induced hepatotoxicity has not been examined. This study investigated the hepatoprotective effects of NGN against DASA-induced acute liver injury, using a mouse model. The mice were given NGN (50, 100, and 200 mg/kg po) or saline for 7 days, followed by DASA on the eighth day (25 mg/kg p.o.). DASA treatment alone was found to cause overexpression of proinflammatory cytokines, such as interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and malonyl aldehyde (MDA), whereas attenuation of antioxidant genes including superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx). Interestingly, a pretreatment with NGN + DASA resulted in minimizing the proinflammatory mediators and restoring the levels of antioxidant genes. In addition, there was evidence of necro-inflammatory changes in histopathological findings in the liver samples after DASA administration which remarkably reduced with NGN + DASA. Thus, this study revealed that NGN could minimize the hepatotoxicity induced by DASA by providing anti-inflammatory and antioxidant protection.
达沙替尼（DASA）是一种新型酪氨酸激酶抑制剂，已被批准用于白血病治疗。然而，长期使用达沙替尼会引发多种并发症，尤其是肝损伤。另一方面，柚皮素（NGN）是一种有效的抗氧化剂和抗炎剂，已知在多种肝病动物模型中发挥保护作用。然而，柚皮素对达沙替尼诱导的肝毒性的影响尚未得到研究。本研究使用小鼠模型，研究了柚皮素对达沙替尼诱导的急性肝损伤的肝保护作用。给小鼠口服柚皮素（50、100和200mg/kg）或生理盐水，持续7天，在第8天给予达沙替尼（25mg/kg口服）。单独使用达沙替尼治疗会导致促炎细胞因子如白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）和丙二醛（MDA）的过度表达，而抗氧化基因如超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽S-转移酶（GST）和谷胱甘肽过氧化物酶（GPx）的水平则会降低。有趣的是，用柚皮素+达沙替尼预处理可使促炎介质减少，并恢复抗氧化基因的水平。此外，有证据表明，在给予达沙替尼后，肝脏样本的组织病理学检查结果出现坏死性炎症变化，而柚皮素+达沙替尼可使其显著减轻。因此，本研究表明，柚皮素可通过提供抗炎和抗氧化保护作用，将达沙替尼诱导的肝毒性降至最低。
