Hepatoprotective Effect of Pericarpium zanthoxyli Extract Is Mediated via Antagonism of Oxidative Stress

Abstract

Pericarpium zanthoxyli has been extensively used in traditional Oriental medicine to treat gastric disorders and has anti-inflammatory and antioxidative activities. Therefore, the present study examined a possible hepatoprotective effect of a P. zanthoxyli extract (PZE) and investigated the underlying molecular mechanisms. We employed an in vitro model of arachidonic acid (AA) + iron-induced hepatocyte damage and an in vivo model of CCl4-induced liver injury to assess the effects of PZE and evaluated the relevant molecular targets using biochemical assays, flow cytometry analysis, Western blot, and histopathological analysis. The PZE inhibited AA + iron-induced hepatotoxicity in HepG2 cells, improved mitochondrial dysfunction, and reversed an increase in the cellular H2O2 production and a decrease in the reduced GSH levels induced by AA + iron. Treatment with either 30 or 100 μg/ml PZE significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and the latter dose also increased the antioxidant response element- (ARE-) driven luciferase activity and enhanced the protein expressions of glutamate-cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. In addition, treatment with 100 μg/ml PZE for 3 or 6 h increased the phosphorylation rates of Nrf2 and the extracellular signal-regulated kinase. In the in vivo experiment, oral treatment with both 100 and 300 mg/kg PZE inhibited the plasma aspartate aminotransferase activity, and the latter also inhibited the plasma alanine aminotransferase activity. In addition, both doses of PZE ameliorated the parenchymal degeneration and necrosis in the liver induced by CCl4 administration, which was associated with reduced expressions of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, nitrotyrosine, and 4-hydroxynonenal by PZE. These findings suggest that PZE has protective effects against hepatotoxicity both in vitro and in vivo, which are mainly mediated via its antioxidant activity.