Related Experiment Video
Updated: Aug 23, 2025
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Hepatotoxic metabolites in Polygoni Multiflori Radix- Comparative toxicology in mice
Shixiao Wang1,2, Xiang Kong1,2, Ning Chen1,2
1Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, China.
Abstract:
Polygoni Multiflori Radix (PM) and Rhei radix et rhizoma (rhubarb) contain similar hepatocyte-toxic anthraquinones such as emodin (major free anthraquinone in PM), physcion and their glycosides. In clinical practice, PM hepatotoxicity has been widely reported, although rhubarb is not recognized as hepatotoxic. To clarify the substances basis (key components) of PM hepatotoxicity, based on the characteristic components' similarity within PM, rhubarb and their concocted forms, a comparative sub-acute toxicity study was designed in mice. Nine groups of mice with 28 days of oral administration of these herbal extracts or 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG, major and unique characteristic component in PM)-herb combinations were set as follows: Group-1, control; Group-2, PM ethanol-extract (PME); Group-3, PM praeparata ethanol-extract (PMPE); Group-4, Rhubarb ethanol-extract (RME); Group-5, Steamed rhubarb ethanol-extract (RMPE); Group-6, TSG; Group-7, PMPE-TSG combination; Group-8, RME-TSG combination; Group-9, RMPE-TSG combination. Each experimental group received an equivalent emodin dose of 29 mg/kg except for the TSG group, and an equivalent TSG dose of 1,345 mg/kg except for the PMPE, RME and RMPE groups. The results showed that PME, PMPE-TSG and RME-TSG induced liver lesions and biochemical abnormalities of liver function compared with the control. In contrast, PMPE, RME, RMPE, TSG and RMPE-TSG caused no liver lesions and fewer biochemical abnormalities. Considering the related components, only the co-administration of high doses of TSG and emodin-8-O-β-D-glucoside (EMG, major anthraquinone glycoside in PM) in these groups could cause liver lesions. According to tissue distribution and correlation analysis, EMG dose was positively correlated with the high hepatic emodin and TSG exposure, and the hepatic emodin and TSG exposure were positively correlated with the biochemical abnormalities of liver function. Cell viability test in vitro showed emodin was more hepatotoxic than TSG and EMG, and mainly emodin and TSG of the three had synergistic hepatotoxic effects. Therefore, creatively using rhubarb as a reference, this study revealed that PM hepatotoxicity in mice mainly came from the integrative contribution of TSG, EMG and emodin.
Insights
Hepatotoxicity of Polygoni Multiflori Radix (PM) in mice was investigated. The study found that PM hepatotoxicity is mainly caused by the combined effects of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin-8-O-β-D-glucoside (EMG), and emodin.
Area of Science:
- Pharmacology
- Toxicology
- Herbal Medicine Research
Background:
- Polygoni Multiflori Radix (PM) is associated with reported hepatotoxicity, despite containing similar anthraquinones to Rhei radix et rhizoma (rhubarb), which is not recognized as hepatotoxic.
- Understanding the specific components responsible for PM-induced liver injury is crucial for clinical safety.
Purpose of the Study:
- To identify the key components contributing to PM hepatotoxicity by comparing PM and rhubarb extracts and their combinations with specific compounds in a mouse model.
- To elucidate the synergistic or individual toxic effects of characteristic components like TSG, EMG, and emodin on liver function.
Main Methods:
- A 28-day sub-acute toxicity study in mice using oral administration of PM and rhubarb extracts, steamed rhubarb extracts, isolated 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), and their combinations.
- Groups were administered equivalent doses of emodin and TSG, with toxicity assessed through liver lesions and biochemical markers of liver function.
- In vitro cell viability assays were performed to evaluate the individual and combined hepatotoxicity of emodin, TSG, and emodin-8-O-β-D-glucoside (EMG).
Main Results:
- Oral administration of PM ethanol extract (PME), PMPE-TSG combination, and RME-TSG combination induced significant liver lesions and biochemical abnormalities.
- Steamed rhubarb extract (PMPE, RME, RMPE), TSG alone, and the RMPE-TSG combination showed minimal liver toxicity.
- Correlation analysis indicated that high hepatic exposure to emodin and TSG, influenced by EMG dose, was positively associated with liver function abnormalities, with emodin and TSG exhibiting synergistic hepatotoxic effects in vitro.
Conclusions:
- PM hepatotoxicity in mice is primarily attributed to the integrated contribution of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin-8-O-β-D-glucoside (EMG), and emodin.
- The processing of PM (steaming) and rhubarb appears to reduce their hepatotoxic potential.
- This study highlights the importance of considering the combined effects of multiple compounds in assessing the safety of herbal medicines.
