A comprehensive survey of warfarin-induced hepatic toxicity using histopathological, biomarker, and molecular...

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.