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Precise subcellular organelle-targeted analyses of hepatotoxicity of Polygonum multiflorum
Yijie Li1, Shuni Duan2, Yinhao Zhang1
1School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China.
Objective:
Drug-induced liver injury (DILI) is an undesirable reaction caused by drugs, herbal medicines or supplements and may lead to acute liver failure. Polygoni Multiflori Radix (PMR, Heshouwu in Chinese) originated from the roots of Polygonum multiflorum is a popular traditional Chinese medicine (TCM) while potential hepatotoxicity limits its clinical application. The present study aims to elucidate the in-depth mechanism of PMR-induced organelle heterogeneity of hepatotoxicity.
Methods:
Network pharmacology and available TCM transcriptomics databases including Integrated Traditional Chinese Medicine (ITCM) and HERB databases were conducted to identify the active ingredients of PMR with the potent ability to injure organelles including microsome, mitochondria, endoplasmic reticulum (ER), Golgi apparatus (GA), and lysosome. Organelles were isolated and cultured with adenosine triphosphate (ATP)-supplemented system. Western blotting and particle size characterization techniques were further performed to clarify the organelle heterogeneity of PMR-induced hepatotoxicity.
Results:
Five representative organelles were isolated from mouse livers or hepatocytes and administrated with PMR-derived active components and monomers. The results of network pharmacology and virtual screening initially identified the components of PMR that may damage different organelles. By combining experimental verification, we found that five organelles studied in this research were the target organelles for flavonoid (FVN)'s affiliated compound quercetin (QC). Mitochondria were damaged mainly by kaempferol, anthraquinone (AQ) and its monomeric components. Meanwhile, QC and emodin showed effective toxicity on endoplasmic reticulum. For microsome, QC remained the most toxic monomer. For Golgi apparatus, trans-stilbene glycosides (trans-SG), AQ and emodin were the major toxic components in PMR. For lysosomes, total-SG, emodin and QC were the major toxic components in PMR.
Conclusion:
Collectively, our findings revealed the organelle heterogeneity of PMR-induced hepatotoxicity and identified quercetin as a potential toxic component in PMR. This study provides a novel conjunct strategy to screen and discover potential toxic components and shapes the understanding of toxicity warning and clinically safe use of herbal medicines such as PMR.
Insights
Polygoni Multiflori Radix (PMR) can cause drug-induced liver injury by damaging various organelles. Quercetin was identified as a key toxic component, highlighting the need for careful clinical use of this traditional Chinese medicine.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Drug-induced liver injury (DILI) is a significant clinical concern, often leading to acute liver failure.
- Polygoni Multiflori Radix (PMR), a traditional Chinese medicine, possesses potential hepatotoxicity that limits its widespread clinical application.
- Understanding the specific mechanisms of PMR-induced liver damage is crucial for ensuring its safe use.
Purpose of the Study:
- To elucidate the in-depth mechanism of PMR-induced organelle heterogeneity in hepatotoxicity.
- To identify the specific active components of PMR responsible for damaging different liver organelles.
- To provide a basis for toxicity warning and the clinically safe application of PMR.
Main Methods:
- Network pharmacology and TCM transcriptomics databases (ITCM, HERB) were used to identify PMR's active ingredients.
- Isolation and culture of five key organelles (microsome, mitochondria, ER, Golgi, lysosome) from mouse livers or hepatocytes.
- Western blotting and particle size characterization were employed to assess PMR-induced organelle damage.
Main Results:
- Network pharmacology and virtual screening identified PMR components that damage specific organelles.
- Quercetin (QC) was identified as a primary toxic component affecting flavonoids, microsomes, endoplasmic reticulum, and lysosomes.
- Mitochondria were primarily damaged by kaempferol and anthraquinone (AQ) components, while Golgi apparatus was affected by trans-stilbene glycosides (trans-SG), AQ, and emodin.
Conclusions:
- This study reveals the organelle heterogeneity of PMR-induced hepatotoxicity.
- Quercetin is identified as a significant toxic component within PMR.
- The findings offer a novel strategy for identifying toxic components in herbal medicines and inform safe clinical use.
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