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

PPⅥ² and PPⅦ³ were a group of Pennogenin compounds extracted from the Paris polyphylla and caused hepatotoxicity in human, while the potential underlying mechanism was unclear.

To evaluated the adverse effects of PPⅥ and PPⅦ on the liver in the zebrafish.

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.

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.

This study was the first investigation to provide the direct evidence of hepatotoxicity of PPⅥ and PPⅦ 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.