Atia Mona M, Mahmoud Heba Allah Ahmed, Wilson Magdy, Abd-Allah Elham A
Laboratory of Molecular Cell Biology, Zoology Department, Faculty of Science, Assiut University, Egypt.
Plant Protection Research Institute (PPRI), Agriculture Research Center, Animal Pests Department, Egypt.
Heliyon. 2024 Feb 18;10(4):e26484. doi: 10.1016/j.heliyon.2024.e26484. eCollection 2024 Feb 29.
Warfarin finds human application as anticoagulant therapy. Warfarin usage can cause liver damage and hemorrhage. Besides functioning as anticoagulant and causing continuous bleeding of pests, the mechanism of toxicity of warfarin is unknown. In this study, Wild female and male rats were administrated orally with warfarin for 18 days at 9, 18, 27.5, and 55 mg/kg, respectively. Hepatoxicity was determined by assessing, LD50, leukocyte counts, immunochemistry, histopathology, serum proteins, Western blotting, especially of markers of liver injury, such as AST, ALT & ALP, and markers of antioxidant and oxidative stress markers. Warfarin treatment decreased Nrf2 levels while it increased caspase 3, CYP2C9, COLL1A1. It caused cellular damage and fibrosis of liver. The plasma levels of markers of liver injury, AST, ALT, ALP, bilirubin and transferrin were increased. The plasma levels of albumin, IgG and antitrypsin were decreased. Warfarin treatment decreased RBC and total lymphocyte count while increasing selectively neutrophils. Warfarin exposure caused increased oxidative stress; increased LPO and decreased GSH, SOD, CAT and NO production. Oral exposure of rats with Warfarin leads to increased oxidative stress resulting into liver damage via CYP2C9 mediated by Nrf2 depletion.
华法林在人类中用作抗凝治疗。华法林的使用会导致肝损伤和出血。除了作为抗凝剂发挥作用并导致害虫持续出血外，华法林的毒性机制尚不清楚。在本研究中，分别以9、18、27.5和55mg/kg的剂量对野生雌性和雄性大鼠口服华法林18天。通过评估半数致死剂量（LD50）、白细胞计数、免疫化学、组织病理学、血清蛋白、蛋白质印迹法，特别是肝损伤标志物如天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和碱性磷酸酶（ALP）以及抗氧化剂和氧化应激标志物来确定肝毒性。华法林治疗降低了核因子E2相关因子2（Nrf2）水平，同时增加了半胱天冬酶3、细胞色素P450 2C9（CYP2C9）、I型胶原蛋白α1（COLL1A1）。它导致肝脏细胞损伤和纤维化。肝损伤标志物AST、ALT、ALP、胆红素和转铁蛋白的血浆水平升高。白蛋白、免疫球蛋白G（IgG）和抗胰蛋白酶的血浆水平降低。华法林治疗降低了红细胞和总淋巴细胞计数，同时选择性地增加了中性粒细胞。华法林暴露导致氧化应激增加；脂质过氧化（LPO）增加，谷胱甘肽（GSH）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和一氧化氮（NO）生成减少。大鼠口服华法林导致氧化应激增加，通过Nrf2耗竭介导的CYP2C9导致肝损伤。
