Polygoni Multiflori Radix (He Shou Wu) is a Chinese medicine widely used in clinical treatment and preventive healthcare. However, recently there have been frequent reports of liver injury caused by Polygoni Multiflori Radix and its related preparations, and some patients have serious adverse outcomes, attracting wide attention worldwide. The risk of liver damage caused by preparations containing Polygoni Multiflori Radix or Polygoni Multiflori Caulis has been repeatedly reported by the Chinese Food and Drug Administration. Fortunately, substantial progress has recently been made in revealing the basic properties, main causes, material basis, and molecular mechanism of Polygoni Multiflori Radix-related liver injury. The basic characteristics and biomarkers of susceptible people have been identified, indicating that Polygoni Multiflori Radix has the risk of inducing liver injury only in a few specific populations and is safe for most populations. This study provides a scientific basis for a correct and objective understanding of liver injury caused by Polygoni Multiflori Radix, and a reasonable formulation of safe medication measures for Polygoni Multiflori Radix and related preparations. The China Association of Chinese Medicine organized experts in relevant fields across the country to draft and formulate the “Guidelines for Safe Use of Polygoni Multiflori Radix” with the aim of helping the public and relevant institutions at home and abroad to scientifically understand, evaluate, and avoid the risk of liver injury; guide the rational use; protect the health rights and interests of consumers; and promote the healthy and sustainable development of Polygoni Multiflori Radix and related preparations. These guidelines were issued by the China Association of Chinese Medicine (No. T/CACM 1328-2019).
Today, as the use of traditional Chinese medicine (TCM) becomes widespread globally, TCM is confronted with numerous new safety issues and challenges. In particular, the frequent emergence of safety issues/events such as liver and kidney injury associated with traditionally “non-toxic” TCM has overturned the conventional understanding of the toxicity and safety of TCM. This has also posed significant challenges to the development and internationalization of TCM. So, how should we understand the situation and problems of TCM safety? How can we scientifically solve the problems in evaluation and risk control of TCM? Our team proposes the following: First, we must keep pace with the times and view the issues of TCM safety in a dialectical manner, without exaggeration or underestimation. Second, we must break through the traditional perception that toxicity only came from the medicine itself, and innovate the theories of TCM toxicity. Third, we must establish precise prevention and control strategies for TCM with different types of toxicity, promoting a shift in the management of TCM safety risks from passive response to scientific and proactive control. On this basis, we have put forward the concept and methodological system of the “New Outlook on TCM safety”, hoping to provide new theories, strategies, methods, and successful examples for systematically solving the problems in the evaluation and risk control of TCM.
Psoraleae Fructus, the dried mature fruit of the leguminous plant Psoralea corylifolia L., contains flavonoids, coumarins, monoterpene phenols, and benzofurans. It exhibits various pharmacological activities, including immune regulation, antioxidant properties, photosensitivity, and estrogen-like effects, and finds extensive use in the clinical treatment of osteoporosis, vitiligo, and psoriasis. Extensive pharmacological research has demonstrated that Psoraleae Fructus and its components improve liver function and protect hepatocytes in animal and cellular models of liver diseases. Moreover, with the increasing clinical applications of Psoraleae Fructus and its derivatives, as well as the progression in adverse drug reaction surveillance, there is an increase in clinical cases involving these preparations and the enhancement of monitoring for any adverse reactions linked to Psoraleae Fructus and its related compounds. Here, we examined the hepatoprotective effects and hepatotoxicity of the monomer components, extracts, and related preparations of Psoraleae Fructus. We aim to contribute to safety evaluation, facilitate informed clinical application, and foster advancements in Psoraleae Fructus and its derivatives.
Ensuring the safety of traditional Chinese medicines (TCM) has perennially presented a universal challenge in the healthcare realm. Meticulous investigations into the toxicological intricacies of natural products are of paramount significance, particularly regarding the metabolic transformation of these substances and the subsequent generation of reactive intermediates. This biochemical process underlies the genesis of diverse toxic manifestations, including hepatotoxicity, nephrotoxicity, pulmonary toxicity, and genotoxicity. Compounds sorted within TCM, including pyrrolizidine alkaloids, anthraquinones, furanoterpenoids, alkenylbenzenes, bisbenzylisoquinoline alkaloids, flavonoids, and methylenedioxyphenyl derivatives, evince a spectrum of deleterious mechanisms upon metabolic activation. This review provides a comprehensive delineation of the pathways through which these compounds induce toxicity via metabolic activation. This review emphasizes the chemical mechanisms involved in the metabolic activation of natural products that may trigger a toxic cascade, rather than a superficial phenomenon. Furthermore, this study enriches the extant literature by delving into advancements in elucidating the mechanisms of toxicity engendered by metabolic activation. In conclusion, this review highlights the importance of scrutinizing the mechanisms of toxicity and provides insights into the judicious and safe use of TCM.
Asari Radix et Rhizoma (ARR), also known as Xixin, has been broadly used as a traditional herbal medicine in East Asia and is an important component of classic prescriptions, including Mahuang Fuzi Xixin decoction. It was initially classified as a “top grade” herb in ancient Chinese Pharmacopeia, Shennong’s Materia Medica. Volatile oils, lignans, fatty acids, flavonoids, and nitrogen-containing compounds are the main ARR components. Previous pharmacological studies have shown that ARR exerts beneficial effects in humans for treating headaches, toothaches, and several inflammatory diseases by dispelling wind and cold, alleviating pain, and eliminating phlegm. However, “the dosage of ARR should not exceed one coin (approximately 3.75 grams),” as stated in Shizhen Li’s Compendium of Materia, which emphasized the considerable ARR toxicity and significantly constrained its clinical application. This review aimed to consolidate recent advancements in the understanding of the toxic ARR components. Additionally, we provide an overview of the hepatotoxicity, genotoxicity, neurotoxicity, and pulmonary toxicity of ARR and discuss the underlying molecular mechanisms. This study reviews the limitations of current studies and enhances our understanding of the toxic effects of ARR from the perspective of its toxic components and mechanisms, thereby providing a theoretical basis for the rational clinical practice of ARR-based medications.
Objective: Polygonum multiflorum Thunb. (PM) is a commonly used tonic herb known to cause idiosyncratic drug-induced liver injury (IDILI). This study explored the detoxification effects and potential mechanisms of action of Paeoniae Radix Alba (PRA) on PM-induced IDILI.
Methods: Network pharmacology analysis was utilized to predict the related targets of “PRA-PM-innate immunity.” A non-hepatotoxic lipopolysaccharide (LPS) and PM-induced IDILI model was used to evaluate the detoxification effects of PRA by measuring liver function indicators, pathological examinations, and macrophage-related factors. Bone marrow-derived macrophages (BMDMs) were stimulated with IL-4 to differentiate into M2 macrophages, and the effects of PM and PRA on M2 macrophage polarization were explored.
Results: Target screening of “PRA-PM-innate immunity” identified 21 intersecting targets, most of which were closely associated with macrophage polarization. In rat models of IDILI induced by PM, the combined use of PRA significantly reduced the extent of liver damage and the levels of inflammatory factors, while promoting the expression of M2 macrophage-related factors such as interleukin (IL)-4, IL-10, arginase 1 (Arg1), and CD206. In vitro, PM dose-dependently inhibited the expression of the Arg1 protein and M2 macrophage-related genes, whereas PRA exhibited the opposite effect. When used in combination, PRA ameliorated the inhibitory effect of PM on M2 macrophage polarization.
Conclusions: Our results demonstrate that PRA has a therapeutic effect on PM-induced IDILI; its mechanism may involve alleviating liver injury by promoting M2 macrophage polarization, thus reducing the expression of inflammatory factors.
Objective: Xianling gubao (XLGB), a widely used Chinese patent medicine for osteoporosis, has garnered significant attention due to its potential to cause liver injury. The constituents Psoraleae Fructus (PF, the dried ripe seeds of Psoralea corylifolia L.) and Epimedii Folium (EF, the dried leaves of various Epimedium species) present in XLGB have been implicated in causing idiosyncratic drug-induced liver injury (IDILI). However, the specific components and mechanisms underlying liver injury related to these tonics remain elusive. This study aims to establish that the combination of bavachin (the primary active compound in PF, and icariside II, the main active compound in EF) induces IDILI in a tumor necrosis factor-α (TNF-α)-mediated mouse model.
Methods: To assess the impact of bavachin and icariside II on the liver in the presence of TNF-α immune stress, an animal model was developed. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics technology was employed to identify biomarkers associated with TNF-α-induced IDILI and the combination of bavachin and icariside II. Additionally, 16S rRNA high-throughput sequencing technology was utilized to explore changes in the species composition and relative abundance of gut microbiota. Spearman correlation analysis was conducted to unveil the relationship between gut microbiota and in vivo metabolites.
Results: The study observed that the combined administration of bavachin and icariside II induced liver injury in the TNF-α mediated susceptibility mouse model of IDILI. Under TNF-α stimulation, there was an elevation in levels in mouse livers following bavachin and icariside II administration, while Gly-Tyr, Leu-Gly, and Trp-Ser levels decreased. These differentially expressed metabolites associated with liver injury were predominantly enriched in metabolic pathways such as sphingolipid metabolism, sphingolipid signaling pathway, and necroptosis. it is noteworthy that the gut of mice with liver injury induced by the bavachin and icariside II combination exhibited a significant increase in Bacteroides and Desulfovibrionaceae abundance. Correlation analysis revealed a positive association between Bacteroidaceae and Desulfovibrionaceae with methylcarbamoyl PAF and methyl Indole-3-acetate, while a negative correlation was observed with Gly-Tyr, Leu-Gly, and Trp-Ser.
Conclusions: These findings demonstrated that the combination of bavachin and icariside II increased the risk of IDILI in vivo, providing a promising scientific basis for understanding the component basis of IDILI resulting from the compatibility of EF and PF.
Objective: To compare the acute toxicity and chemical ingredients of Psoraleae Fructus (PF) with those of two classic prescriptions, Ershen Wan (ESW) and Sishen Wan (SSW).
Methods: Based on classical toxicological methods, body weight, food and water consumption, lethal conditions, and toxic reactions were recorded after administering single oral doses of PF, ESW, and SSW. The 50% lethal dose (LD50) values of PF and ESW and the maximum tolerance dose (MTD) of SSW were determined. In addition, PF, ESW, and SSW constituents were detected using ultra-high-performance liquid chromatography/mass spectrometry (UPLC-MS), and the spectrum-toxicity correlation was analyzed.
Results: The LD50 of PF and ESW were 53.9 g/kg/day (46.2-63.0 g/kg/day, 95% confidence limit [CL]) and 68.3 g/kg/day (59.0-78.9 g/kg/day, 95% CL), which were respectively about 40 and 50 times the human daily dosage. The MTD of SSW was 41.0 g/kg/day, indicating the highest safety. What can be inferred from the chemical ingredients and toxicity correlation analyses is that compatibility reduced the contents of 13 potential hepatotoxin compounds in PF.
Conclusions: The classic compatibility of ESW and SSW effectively attenuated the hepatotoxicity of PF, which was related to the reduced content of potentially toxic substances, particularly coumarins. This study explored the principles of attenuating the toxicity of classic prescriptions to provide a reference for the rational clinical use of PF.
Objective: Drug-induced liver injury (DILI) is the leading cause of acute liver failure and poses a significant challenge to human health. Rhubarb (Rheum officinale Baill. DaHuang) has been clinically used for its heat-clearing and diuresis-promoting effects. However, its toxic effects on different organelles in the liver require further validation.
Methods: We analyzed the potential targets affecting hepatotoxicity in rhubarb and the potential damage relationship with five major organelles, including microsomes, mitochondria, endoplasmic reticulum (ER), Golgi apparatus (GA), and lysosomes through Integrated Traditional Chinese Medicine (ITCM)/HERB databases and network pharmacology. We isolated and purified different organelles, incubated them with different fractions and monomers of rhubarb in an adenosine triphosphate (ATP) culture system and examined the structural and functional changes in the organelles using particle size analysis and molecular biological experiments to investigate whether rhubarb affects the damage and rupture of major organelles in the liver.
Results: By combining virtual predictions and experimental verification, our research confirmed that emodin isolated from the anthraquinone of rhubarb, catechin in the tannins of rhubarb, and palmitic acid in the organic acids of rhubarb caused the most significant functional and structural damage to the representative organelles. Among all the monomeric compounds, emodin caused the most damage to the microsome, mitochondria, ER, and lysosome; catechin induced microsome and GA damage; and palmitic acid caused the most damage to microsomes and GA in the liver, suggesting that rhubarb components may exert hepatotoxicity through multi-organelle injury.
Conclusions: Our findings revealed that rhubarb has varying degrees of damaging effects on different organelles, which in turn affects cellular life activities by impairing organelle morphology and function. This study provides a theoretical basis and technical support for a refined analysis of the toxic components and targets of rhubarb.
Objective: Euodia rutaecarpa, (Wu Zhu Yu) a Chinese medicine clinically used to treat gastrointestinal disorders, has been widely employed. However, Euodia rutaecarpa is regarded as a small toxic traditional Chinese medicine in the Chinese Pharmacopoeia and other herbal works. Using toxicity predictions combined with in vitro and in vivo studies, this study aimed to identify the toxic components and toxic target organs of Euodia rutaecarpa, and explore its toxic mechanism from a metabolic perspective.
Methods: The toxic target organs of Euodia rutaecarpa were identified through in vitro and in vivo studies. In vitro toxicity screening was performed by alkaloid enrichment and isolation. The potential toxicity of compounds was predicted by Absorption, Distribution, Metabolism, Excretion, and Toxicity Predictor (ADMET Predictor) based on Quantitative Structure-Activity Relationship (QSAR) construction. In addition, the study integrated the serum metabolomic analysis after the administration of potentially toxic components to clarify the effect of potentially toxic substances on metabolism in mice.
Results: Comparing the acute toxicity in mice of different extraction methods and before and after processing, it was evident that Euodia rutaecarpa alcoholic extract had the highest toxicity, and the target organ of Euodia rutaecarpa toxicity was the liver. The alkaloid fraction of alcoholic extract of Euodia showed strong cytotoxicity. The potential toxicity of Euodia rutaecarpa was calculated and predicted by ADMET Predictor, and alkaloids are suspected to be responsible for the toxicity of Euodia rutaecarpa. Evodiamine significantly reduced the number of cells and increased the mitochondrial membrane potential in vitro. Different metabolites were significantly identified by serum metabolomics, of which bile acid metabolism and steroid hormone biosynthesis are the key pathways of hepatotoxicity.
Conclusions: Clarify the scientific significance of clinical use of processed products by comparing the acute toxicity of different extraction methods before and after processing. Combining the toxicity prediction based on QSAR with the toxicity screening in vitro and in vivo, the potential toxic target organs and toxic components of Euodia rutaecarpa can be identified. Through metabolomics, we preliminarily revealed that the hepatotoxicity of Euodia rutaecarpa may be related to bile acid metabolism and steroid hormone biosynthesis. This study lays the foundation for elucidating the mechanism of Euodia rutaecarpa and evaluating its safety and quality.
In recent years, adverse reactions and events associated with traditional Chinese medicines (TCM) and herbal medicines (HM) have frequently occurred. In particular, with regard to the safety of newly discovered TCM that have been deemed “toxic,” providing a scientifically based answer and developing effective solutions is challenging. Owing to the complexity of TCM/HM products and lack of systematic research, our understanding of the potential causes of TCM/HM-induced liver injury is limited. Therefore, significant advancements in understanding the toxicity of TCM and preventing and managing safety risks are urgently needed to address the safety concerns associated with TCM/HM. Using Polygoni Multiflori Radix (PMR) hepatotoxicity as a typical example, we evaluated the “integrated evidence chain” based on the causality evaluation of TCM-induced liver injury, and confirmed the objective authenticity of PMR hepatotoxicity. Furthermore, we first proposed and established a disease-syndrome-combined toxicology model that was applied to the material basis and analysis of the mechanism of PMR-induced hepatotoxicity. The mechanism hypothesis of “three-factor-induced toxicity” of idiosyncratic hepatotoxicity of TCM was proposed and confirmed. Based on this, the disease characteristics of the population susceptible to PMR idiosyncratic hepatotoxicity were elucidated, and various biomarkers were screened and identified, including the genetic marker HLA-B*35:01 and immunological and metabolomic markers. Finally, the study explored and established a safe medication strategy and method for “host-drug-use” three-dimensional risk prevention and control based on identifying susceptible individuals, controlling susceptible substances, and clinical precision medication. This study provides a foundation for comprehensively understanding the scientific implications of TCM/HM toxic side reactions and establishing scientific and effective risk prevention and control strategies.