Investigation of the protective effects of vitamin E on methotrexate induced liver toxicity via SIRT 1, Nrf-2, Keap-2, HO-1 pathways

Drug induced liver injury (DILI); may result to many clinical conditions such as elevated transaminase levels, hepatitis, hepatocellular necrosis, cholestasis, steatotic liver disease and liver cirrhosis. DILI is one of the common adverse drug reactions (ADR) and drug trials are significantly decreasing as a result of the difficulties encountered from ADR. New treatment approaches for the prevention of DILI are gaining importance, and in this study, the potential protective effects of vitamin E on methotrexate-induced liver injury were investigated. For this purpose, in our study; a total of 32 female Wistar Albino rats were randomly divided into four groups, with 8 rats in each group. The control group was administered intraperitoneal (i.p) physiological saline (SF) for five days. The methotrexate (MTX) group received i.p MTX at a dose of 20 mg/kg on the first day, followed by saline for five days throughout the study. The MTX+vitamin E group received MTX only on the first day and 100 mg/kg vitamin E was administered i.p for five days throughout the study. The vitamin E group was administered vitamin E for 5 days. At the end of the 5th day, two hours after the last drug administration, rats in all groups were sacrificed. The obtained liver tissues were analyzed biochemically for total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI); histopathologically for hyperemia, hemorrhage, inflammation, and necrosis scores; immunohistochemically for tumor necrosis factor-alpha (TNF-α) and caspase-3; and genetically for sirtuin1 (SIRT1), nuclear factor erythroid 2-related factor-2 (Nrf2), Kelch-like ECH-associated protein1 (Keap1), and heme oxygenase-1 (HO-1) gene expressions. In the MTX group, biochemically increased TOS and OSI values, decreased TAS value were detected; at the histopathologically level, impairment of liver tissue integrity; immunohistochemically increased inflammation and apoptosis markers were detected; and genetically decreased SIRT1, Nrf2, Keap1 and HO-1 gene expressions were detected. In the MTX+vitamin E group, significant improvements were observed in the detected pathological parameters. In light of these findings, it was concluded that vitamin E had a protective effect on methotrexate-induced liver toxicity and that this effect occurred by regulating oxidative stress, inflammation and apoptosis mechanisms.