Erk1/2, CDK8, Src and Ck1e Mediate <i>Evodia rutaecarpa</i> Induced Hepatotoxicity in Mice

Abstract

Evodia rutaecarpa (E.R.) is a commonly used Chinese herbal medicine. However, it exerts certain hepatotoxicity and the underlying molecular mechanism has not been clarified. In this study, we investigated the molecular mechanism involved in hepatotoxicity induced by E.R. Mice were treated with E.R. water- and ethanol-extract at dosage equivalent to 16.67 g crude-drug/kg body weight by intragastric administration once a day on 30 consecutive days. The effect of E.R. extract on liver, manifested by histopathologic effects, liver index, and blood biochemical indexes were tested. In addition, interleukin (IL)-1 β , IL-6, IL-8, and tumor necrosis factor (TNF)- α in liver tissue were measured. The signaling transduction molecules were determined by antibody microarray assay, and verified by western blot. E.R. extract, either water- or ethanol-extract, can induce liver dysfunction. Signaling molecules, Erk1/2, Src, CDK8 and CK1e, were involved in this process. E.R. extract can induce Ck1e expression and phosphorylation of Erk1/2 and CDK8, and inhibit Src phosphorylation. Inflammatory cytokines in liver tissue, IL-1 β , IL-6, IL-8, and TNF- α were markedly increased upon the treatment of E.R. extract. In conclusion, E.R.-induced hepatotoxicity was due to the expression of inflammatory cytokine, which was mediated through Erk1/2, Src, CDK8 and CK1e.