Protective effects of phloridzin against methotrexate-induced liver toxicity in rats

Background: Liver is the largest internal organ concerning with metabolism, hormonal balance and clarifying of the toxins. One of the main complications of methotrexate (MTX) therapy was the hepatic injury. Objective: This study was conducted to elucidate the possible protective effects of phloridzin (PHL) against MTX-induced hepatotoxicity as compared to standard agent N-acetylcysteine (NAC). Materials and methods: Rats were randomly divided into a normal control group, a respective group (PHL 40 mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20 mg/kg, i.p., once), and three treated groups received NAC (150 mg/kg/day; a reference standard), PHL (40 mg/kg/day) and PHL (80 mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX. Assessed biomarkers included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-II (COX-II), as inflammatory biomarkers, hepatic total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2-), catalase (CAT), glutathione S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings. Results: Rats pre-treated with PHL significantly reduced hepatic injury, evidenced by significant reductions in ALT, AST and LDH, TNF-alpha and COX-II levels, significant reductions in hepatic NO2- and TBARS levels, and significant elevations in hepatic TAC, GSH, GST, CAT and SOD levels. Additionally, downregulation of hepatic caspase-3 expression. Finally, histopathological results consistent with our previous findings. Conclusion: PHL protects against hepatic injury in rats mainly through mitigation of oxidative stress, inflammation and apoptosis in hepatic tissues and may be promising to alleviate and early treatment of MTX-induced hepatoxicity in man.