Hepatotoxicity induced by PPVI and PPVII in zebrafish were related to the Cholesterol disorder.

Abstract Background PPVI 1 and PPⅦ 2 were a group of Pennogenin compounds extracted from the Paris polyphylla and caused hepatotoxicity in human, while the potential underlying mechanism was unclear. Purpose To evaluated the adverse effects of PP VI and PP Ⅶ on the liver in the zebrafish. Method In this study, 4dpf zebrafish were used for acute toxicity test, LC0 was calculated, and 1/2LC0 and 3/5LC0 were selected for pathological section and liver area measurement to verify the hepatotoxicity of PPVI and PPⅦ. Etabonomics study was then conducted to further explore the mechanism of hepatotoxicity of PPVI and PPⅦ. Lovastatin was used as an inhibitor, and PCR was used to verify the results. Result The result showed that under the condition of sub-lethal concentration exposure, hepatotoxicity-included changes in liver phenotype (liver area), hepatocyte swelling and degeneration, liver cell apoptosis and disturbed biochemical index were observed in zebrafish treated with PPVI and PPVII. Furthermore, the transcriptome was conducted to confirm the toxicity mechanism shared with PPVI and PPVII, and we found that steroid biosynthesis process and the related target genes were mainly affected. While, lovastatin treatment effectively ameliorated PPVII-induced zebrafish liver injury by improving the liver tissue structure and regulate the expression of associated genes including HMGCRA, SREBP, LSS, CYP2R1, PIK3R3A, GDPD1 and PFKFB-2. Conclusion This study was the first investigation to provide the direct evidence of hepatotoxicity of PP Ⅵ and PP Ⅶ in vivo zebrafish model, which were related to the steroid biosynthesis. furthermore, in lovastatin played an important role in protection against hepatotoxicity induced by PPVI and PPⅦ by regulating the cholesterol metabolism.