Liver toxicity is a severe problem associated with Traditional Chinese Medicine (TCM). Fructus Meliae Toosendan (FMT) is a known hepatotoxic TCM, however, the toxicological mechanisms of liver injury caused by FMT treatment still remain largely unknown. In this study, we aimed to reveal possible mechanisms of FMT water extract-induced liver injury using a systemic approach. After three consecutive daily dosing of FMT water extract, significant increases of alanine transaminase, aspartate transaminase, and alkaline phosphatase activities, along with elevated total bilirubin and total cholesterol levels and a decrease of triglyceride level, were detected in mice serum. Moreover, hydropic degeneration was observed in hepatocytes, suggesting the presence of FMT-induced liver injury. mRNA and microRNA expression profiles of liver samples from injured mice were analyzed and revealed 8 miRNAs and 1,723 mRNAs were significantly changed after FMT water extract treatment. For the eight differentially expressed miRNAs, their predicted target genes were collected and a final set of 125 genes and 4 miRNAs (miR-139-5p, miR-199a-5p, miR-2861, and miR-3960) was selected to investigate important processes involved in FMT hepatotoxicity. Our results demonstrated several cellular functions were disordered after FMT treatment, such as cellular growth and proliferation, gene expression and cellular development. We hypothesized that liver cell necrosis was the main liver toxicity of FMT water extract, which was possibly caused by oxidative stress responses.

Fructus meliae toosendan-induced liver injury in mice was investigated by integrating the data from miroRNA and mRNA expression profiles combined with the general toxicological assessments method.