Hepatoprotective effects of polymethoxyflavones against acute and chronic carbon tetrachloride intoxication

In the present study, we explore the protective effects of Citrus aurantium L. extract (CAE) against acute and chronic CCl4-induced hepatotoxicity. The quantitative analysis of CAE was performed using HPLC-UV to determine the nobiletin content was approximately 27%. For the acute model, the male ICR mice were orally treated with water, silymarin (positive control, 200 mg/kg) and CAE (50 and 200 mg/kg) for 3 days prior to CCl4 (1 mL/kg, 50% v/v in olive oil) IP injection. For the chronic model (n = 6/group), the mice were treated with each treatment for 28 consecutive days and CCl4 (1 mL/kg, 20%) was injected twice a week. In both the acute and chronic models, the CCl4 alone treated group showed histopathologic alterations with a significantly increase in serum hepatic enzyme levels together with a disrupted anti-oxidative status. In contrast, the CAE treatments restored pathologic alterations and recovered the oxidative status by enhancing antioxidant enzymes and reducing lipid peroxidation levels. Furthermore, CAE enhanced nuclear factor E2-related factor 2 (Nrf2) and its related cytoprotective signals, including NAD(P)H quinone oxidoreductase 1, UDP-glucuronosyltransferase, and γ-glutamylcysteine synthetase. Taken together, the present study demonstrates that CAE exerts a protective effect against CCl4-induced hepatotoxicity with its anti-oxidant, anti-inflammatory, and anti-apoptotic activity.