Liver Toxicity of Rare Ginsenosides in Rats after 13 Weeks of Oral Exposure

Objective: This study aims to evaluate the hepatotoxicity of rare ginsenosides in rats after 90 days of oral administration using heat-transformed rare ginsenosides as the primary material. Methods: A total of 48 male and female rats were randomly assigned into four groups: High-dose rare ginsenosides (600 mg/kg), medium-dose rare ginsenosides (200 mg/kg), low-dose rare ginsenosides (60 mg/kg), and a blank control group. After 90 days of oral gavage treatment, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was employed for metabolomic analysis of rat serum and flow cytometry analysis of liver apoptosis to evaluate the potential liver damage comprehensively in rats. Results: A significant difference in hepatocyte apoptotic rate was observed between the high-dose group and the control group in both male and female rats (P<0.01). Metabolomic findings revealed no significant differences in metabolites between the low-dose and medium-dose groups compared to the control group (P>0.05). However, 23 differential metabolites, such as histidine, glutamate, proline and arginine were identified in the serum of female rats in the high-dose group, affecting the histidine and urea cycle metabolic pathways and causing hyperammonemia and liver damage. Ten differential metabolites affecting the alpha-linolenic acid and linoleic acid metabolic pathways were found in male rats, such as linoleic acid and arachidonic acid. High concentrations of arachidonic acid showed inflammatory and toxic effects, which could be absorbed into the portal vein system through blood and cause liver damage. Conclusion: High-dose rare ginsenosides mainly cause slight liver damage in male and female rats mainly due to the changes of histidine, α-linolenic acid and linoleic acid metabolic pathways. Hence, no adverse liver effects were observed at doses less than 200 mg/kg in both male and female rats.