Dimethyl fumarate ameliorates acetaminophen-induced hepatic injury in mice dependent of Nrf-2/HO-1 pathway

Drug-induced liver toxicity is the most frequent cause of acute liver failure worldwide. Hepatotoxicity caused by acetaminophen (ACT) overdose is mediated by its metabolic product promoting oxidative stress and activation of inflammatory mediators. Nuclear factor erythroid-related factor-2 (Nrf-2) induces the release of cytoprotective enzymes in response to electrophilic or oxidative stress and is considered a promising therapeutic target. Dimethyl fumarate (DMF) is a potent activator of (Nrf-2), its anti-inflammatory and antioxidant properties of DMF have been highlighted recently. We designed this study to explore the effect of DMF (100 mg/kg, orally) administered once and twice on hepatotoxicity induced by acetaminophen (ACT, 500 mg/kg, i. p.) in mice. DMF administration enhanced ACT-induced parameters in liver function, inhibited apoptosis and ameliorated the antioxidant machinery and inflammatory markers in a Nrf-2-dependent fashion. DMF elevated Nrf-2 and HO-1 levels and ameliorated liver injury as indicated by lowered levels of serum aminotransferases, ALP, GGT and bilirubin levels. Hepatic (Bcl-2) was elevated whereas hepatic caspase-3, NF kappa-B, TNF-alpha and MPO were reduced. Hepatic levels of GSH, SOD, MDA and NO were altered promoting the antioxidant machinery. Histological examination of liver has further supported these results. These findings suggest that DMF can be employed in the treatment ACT-induced liver injury acting primarily through targeting Nrf-2/HO-1 pathway.