Toxicological Advances Of Traditional Medicine in 2020
Mar 06, 2022
For more information: emily.li@wecistanche.com
Ya-Ru Li, Shu-Li Man, Long Ma, Wen-Yuan Gao
1 State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China;
2 Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Highlights
1. Liver, kidney, and heart were the main toxic target organs of traditional medicine in 2020.
2. In 2020, zebrafish embryos and Caenorhabditis elegans were popular to evaluate the safety of traditional medicine.
3. The safety assessment of Aconitum Carmichael Debx., Tripterygium wilfordii Hook. f., Polygonum multiflorum Thunb., etc. was still a hot issue in 2020.
Tradition
This annual toxicology review summarized different toxic analysis methods of traditional medicine, evaluated models, toxic target organs, toxic mechanisms, popular research issues, and herbs in 2020.
Abstract
There were many types of research concerning the toxicology of traditional medicine and active natural products during the past 12 months. This annual toxicology review summarized different toxic analysis methods of traditional medicine, evaluated models, toxic target organs, toxic mechanisms, popular research issues, and herbs in 2020. Caenorhabditis elegans came to use for the assessment of toxicity. Omics technology such as genomics, transcriptome, metabolomics, and proteomics was applied extensively.2020 toxicology research demonstrated that the liver, kidney, and heart were the main toxic target organs of traditional medicine. Their toxic mechanisms included cell apoptosis, metabolic disorder, oxidative stress, inflammatory damage, liver and renal fibrosis and even inducing carcinogenesis. In addition, the safety assessment of Aconitum Carmichael Debx., Tripterygium wilfordii Hook. f. and Polygonum multiform Thunb. as well as their detoxification methods were still a hot issue. Therefore, study on the toxicity mechanism of target organs, processing and extract methods, quality control, and dose control, new models and methods should be used in the prevention of traditional medicine toxicology in the future.
Keywords: Traditional medicine, Natural product, Herb, Toxic target organs, Safety evaluation
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Background
Traditional medicine (TM) plays an increasingly important role in medical treatment. In 2020, several papers referred to the toxicity advance of TM such as Polygonum multiflorum Thunb. [1, Triptergium wilfordii Hook. [2]。rhubarb anthraquinones [3] usnic acid(UA)[4], Dioscorea bulbifera L.[5] and so forth. For example, Yuan et al. proposed a new perspective of triptolide-associated hepatotoxicity involved in lipopolysaccharide stimulating NF-kB and NF-KB-mediated cellular FADD-like interleukin beta-converting enzyme inhibitory protein in Acta Pharm Sin B [2]. Li et al. reported that Dioscorea bulbifera L. induced serve hepatotoxicity due to its metabolic activation of furanoditer periods diosbulbin B as well as 8-epidiosbulbin E in Drug Metab Rev [5]. Meanwhile, Superman et al.used a combined in vitro physiologically based kinetic model to predict the liver toxicity of monocrotaline in rats compared with lasiocarpine and ridgeline in Arch Toxicol [6]. They found that monocrotaline causes hepatic toxicity and carcinogenicity attributed to its hepatic metabolic activation by cytochrome P450 (CYP).
At the same time, multiple theories and new detection technologies have been applied. For example, computational tools-silico methods were used to evaluate the hepatotoxicity of kava(Piper methysticum)[7] and monocrotaline [6. The ultra-low adsorption plate and the inverted model were employed to establish a hepatotoxicity evaluation system of Polygonum multiflorum [8]. Omics technology was applied for better understanding the toxic mechanisms of different TM [9]. In 2020, China played a key role in the promotion of the rapid upsurge in TM. The statistical analysis annual publication of toxicological studies on TM by the relative percentage on different countries was shown in Figure 1. The USA ranked the second important country, while Malaysia was tied with India and Morocco ranked the third and fourth place. Moreover, the toxicological evaluation of TM is valuable and important for their rational application.
This review summarized different toxic analysis methods of TM in 2020. The herbs mentioned in this paper should be used with caution. Therefore, study on the toxicity mechanism of target organs, processing and extract methods, quality control, and dose control, new models and methods should be used in the prevention of TM toxicology in the future.
Organ toxicity
The liver was regarded as the top one toxic target organ in TM
The liver, as an important tissue for drug metabolism, is a major toxic target organ for TM. In 2020, there were a large number of researches focusing on the relationship between liver metabolism and hepatotoxicity, including sphingolipid metabolism, phenylalanine metabolism, tyrosine metabolism, and glycerophospholipid metabolism involved in oxidative stress, lipopolysaccharide-induced inflammation, and CYP-catalyzed oxidation of the furan ring.
For example, metabolic pathway analysis showed that Polygonum multiflorum Thunb. disrupted the phenylalanine and tyrosine metabolism and then resulted in primary liver injury. As the administration time went on, Polygonum multiflorum Thunb. induced the alternation of vitamin B6, bile acid, and bilirubin metabolism, and then led to aggravated liver damage ]. The rat primary hepatocyte micro-tissue model system was further proof of the potential hepatotoxic components from Polygonum multiflorous Thunb. belonging to emodin-type monoterpene or rhein. Its metabolites like emodin-8-O-beta-D-glucoside and emodin methyl ether displayed more toxicity [8]. Label-free proteomics indicated that its main compound emodin directly targeted acadyl/complex IV to induce oxidative stress and inhibited fatty acid beta-oxidation, citric acid cycle, and oxidative phosphorylation in liver mitochondria [10]. Furthermore, long-term or high-dose use of emodin reduced the expression of uridine diphosphate-glucuronosyltransferase 2B7 by inhibiting the expression of hepatocyte nuclear factor 4alpha and thereby induced liver damage [11].
Xianling Gubao capsule induced liver injury (constituent herb: Epimedium brevican, Dipsaci Radix, Salvia miltiorrhiza, the approved number by China Food and Drug Administration: Z20025337)belonged to idiosyncratic drug-induced liver injury, which was promoted by mild immune stress induced by the non-toxic dose of lipopolysaccharide and caused metabolic reprogramming, including sphingolipid metabolism, phenylalanine metabolism and glycerophospholipid metabolism [12]. Triptolide is a major active component of Triptergium wilfordii Hook. also induced hepatotoxicity based on lipopolysaccharide-stimulated liver hypersensitivity. Transcriptomics suggested that NF-κB-dependent transcriptional activity and FADD-like interleukin beta-converting enzyme inhibitory protein production should contribute to triptolide-associated liver hypersensitivity [2]. PI3K/AKT, MAPK, TNF-alpha and p53 signaling pathways also participated in triptolide-induced hepatocyte apoptosis [13]. Metabolomics indicated that glycerophospholipid, fatty acid, leukotriene, purine, and pyrimidine metabolic alterations happened after triptolide exposure. Acylcarnitines were identified as potential biomarkers for the early detection of triptolide-induced liver injury [13]. In addition, triptolide pharmacokinetics and circadian expression of hepatic Cyp3a11 were used to explain Tripterygium wilfordii-induced hepatotoxicity [14].
Cortex dictamnus and Dioscorea bulbifera L. contained many furan compounds which were hepatotoxic resulted from the CYP-catalyzed oxidation of the furan ring. For instance, multiple paranoids from Cortex dictamnus such as obakunone, dictamnine, fraxinellone, and limonin were metabolized into reactive epoxide or cis-enedione, thereby inducing liver injury [15]. The main toxic components of Dioscorea bulbifera L. like furanoditer periods diosbulbin B and 8-epidiosbulbin E were mediated by CYP and further reacted with nucleophilic sites of protein and DNA [5], or interacted with polyamines, biogenic amines, and amino acids which were involved in the polyamine metabolic pathway and therefore induced liver cells apoptosis and cell death [16].
Furthermore, serum pharmacochemistry and network toxicology were used to screen the potential hepatotoxic components and possible mechanisms of the processed Radix Aconiti Lateralis. The results obtained a toxicological evidence chain involving its promotion of oxidative stress, metabolic disorders, cell apoptosis, immune response, and excessive release of inflammatory factors [17]. Mouse liver natural cytotoxic T cells in vitro and in vivo model indicated that matrine suppressed cell viability, increased cytotoxicity, and induced apoptosis-related proteins like activated caspase-3 and caspase-9 to induce liver injury [18].
According to the recent reviews in 2020, the kava (Piper methysticum) compounds induced hepatotoxicity through glutathione depletion, CYP inhibition, reactive metabolite formation, mitochondrial toxicity, and cyclooxygenase activity [7]. UA as a hepatotoxin isolated from lichens also induced adenosine triphosphate depletion, decreased glutathione, induced oxidative stress, lipid peroxidation, and organelle stress. However, its mechanisms of pro-inflammatory or anti-inflammatory responses, CYP detoxifying UA into non-toxic or transforming UA into reactive metabolites, and so forth were still unknown [4].
The kidney was considered as the second toxic target organ in TM
Recently, researchers focused on the role of metabolism in the known nephrotoxic TM, including Polygonum multiflorum Thunb., colchicine, and Aristolochia debilis. It’s demonstrated that nephrotoxicity is caused by Polygonum multiflorum Thunb. was dynamic processes that affected different metabolic pathways at different administration times, such as the phenylalanine and tyrosine metabolism [1]. Colchicine inducing kidney impairment was mainly associated with its interaction with CYP3A4 and P-glycoprotein [19]. Meanwhile, the interaction of Aristolochia debilis with the target protein organic anionic transporter 1 plays a key role in mediating aristolochic acid-related nephropathy[20, 21].
Besides, processing methods affected the nephrotoxicity of some TM. For example, although two kinds of pharmacopeia-based boiling and atmospheric steaming methods of Aconiti kusnezoffii Radix had certain damage to the kidney, their toxicity was lower than that of crude herbs [22].
Furthermore, as a food and herbal without potential toxic effect, Hibiscus sabdariffa calyces significantly increased the levels of globulin, urea, creatinine, and atherogenic index in the sub-chronic study [23]. The methanol extract of Tetrorchidium didymostemon significantly increased the genes expression of tumor necrosis factor-alpha and kidney injury molecule-1. It also up-regulated the catalase gene expression especially in the kidney [24]. In addition, the methanol extract of Imperata cylindrica induced nephrotoxicity around the dose of 1 g/kg b.w., which performed a significant variation of the relative kidney index and decrease of aspartate aminotransferase, creatinine level, triglyceride, and total cholesterol [25]. Therefore, these extracts should be used with caution.
Other toxic target organs of TM
As 2020 reported, Radix Aconiti kusnezoffii causing heart rate and Q-T interval changes were evaluated using a toxicokinetic-toxicodynamic model of indirect toxicity [26]. The cardiotoxic mechanism of crude Radix Aconiti Lateralis Preparata was explored and compared with its combination with Glycyrrhiza and prepared materials [27]. Besides, aconitine and mesaconitine inducing arrhythmogenic effects were linked to their increasing the peak INa via accelerating sodium channel activation and inhibiting the INa/K. Mesaconitine displayed a more potent arrhythmogenic effect than aconitine [28]. Moreover, researchers found that the relationship between the therapeutic and toxic doses of these drugs is small and uncontrollable. Chloroquine leads to sudden cardiac death after gastrointestinal poisoning [29]. Additionally, pharmacokinetics and pharmacodynamics were used to analyze digoxin-induced cardiotoxicity in the 2020 review [30].
Furthermore, toxicological properties of the alkali-ethanol extract from Anemone radiant Regel [31], toxic extract parts from Aconitum sinomontanum Nakai roots [32], and Hei-Shun-Pian processed Aconitum Carmichael Debeaux lateral root with peel, [33] were also reported. It’s reported that intestinal toxicity of rhubarb anthraquinones was associated with its pro-apoptosis and pro-autophagy activity [3]. Licorice-Yuanhua herbal pair induced ileum injuries through weakening epithelial and mucous barrier functions [34]. Pulmonary toxicity of pyrrolizidine alkaloids was linked to metabolically activating to form reactive dehydro-PAs, which generated pyrrole-protein adducts [35]. These extracts should be used with caution. Taken together, statistical analysis of annual publication referred to different toxic target organs induced by TM was summarized in Figure 2.
Current advances
Various models were used to evaluate the safety of TM
Right now, the safety evaluation has been applied at cellular, organ & individual levels. Rodents were regarded as the common individual models to analyze the safety of TM or natural products. For example, the toxicity of triptolide was evaluated on renal cells and breast carcinoma stem cells [36]. Its inhibitory effects on the development of choroidal neovascularization were also evaluated in mice [37]
Meanwhile, a zebrafish model was increasingly considered to be a reliable, rapid, medium-throughput, and cost-effective model for the evaluation of embryotoxicity. During 2020, it was used in the toxicity evaluation of Hystrix Brachyura Bezoar [38], Curcuma longa [39], low-molecular-weight chitosan [40], cyclometalated Ru(II) [41], non-digestible oligosaccharides [42] and Antirhea borbonica [43].
Interestingly, Caenorhabditis elegans was first used to access the toxicity effects of Peganum harmala L. seeds. Researchers found that the lethality of Caenorhabditis elegans was significantly increased when they were exposed to the ethanol extract of Peganum harmala L. seeds at 0.25, 0.50, and 1.00 mg/mL (P < 0.01), and the mean lifespan was significantly decreased (P < 0.01). Besides, Peganum harmala L. seeds exposure could induce toxicity on body length, brood size, and locomotion behavior [44]. Except for these, Drosophila [45] was popular in the safety evaluation of various chemical compounds recently. However, there was no research on that in TM. In the future, the application of Drosophila in TM toxicity evaluation can be focused on.
Omics and other new toxicology study technology Recently, the rapid development of omics technology provides new ideas and tools for life science and medical research [9]. For example, a genome-wide association study was applied to reveal the metabolism and toxicity of emodin [11]. Proteomics demonstrated that emodin elicited mitochondrial dysfunction to cause liver oxidative damage [10]. The antihypoxia effect of Salvia przewalskii Maxim. was primarily associated with its antioxidative stress [46]. Furthermore, antiproliferative and anti-inflammatory effects of Tussilago farfara [47], the toxicological effects of cinnabar [48], and hepatotoxic mechanisms caused by Fructus Psoraleae [49] were better understood through using quantitative chemical proteomics. Metabonomics and transcriptomics were used to understand triptolide-induced liver injury comprehensively [13]. Rhododendron and secondary metabolites in the biosynthesis were explored via de novo transcriptome sequencing [50].
Meanwhile, multiple other technologies have been applied in TM toxicity evaluation. For instance, pharmacokinetics were used in the toxicity of Polygalae Radix [51]. Toxicokinetics was utilized to investigate Gelsemium elegans [52]. In addition, in vitro-in silico approach [6], foldscopes [39], nanotechnology [53], and chromatographic fingerprinting [54] were also employed gradually.
Other hot issues in 2020
Recently, researchers not only focused on the safety and toxicity assessment of TM but also paid attention to the safety evaluation of natural food like chitosan [55], fucoidan [56], and fibers. For example, 500 mg/mL of palm kernel cake oligosaccharides appeared toxic to zebrafish larvae [42]. Fermentable fiber induced hepatocellular carcinoma in mice through dysregulating the gut microbiota and inducing cholestasis and hepatic inflammation [57, 58]. Therefore, a recent review summarized the inadequate application of inulin-type fructans aggravated the development of non-alcoholic fatty liver disease, resulting in gastrointestinal symptoms, liver cancer, and intestinal inflammation [59].
Conclusion
Taken together, the effect-toxicity-chemical study, toxicokinetics, foldscopes, silico methods, and omics technology have been used in toxicology research since 2020. Besides rodents and zebrafish embryos, Caenorhabditis elegans came to use for the assessment of TM toxicity. 2020 toxicology research demonstrated that the liver, kidney, and heart were the main toxic target organs of TM. Their toxic mechanisms included cell apoptosis, metabolic disorder, oxidative stress, inflammatory damage, liver and renal fibrosis and even inducing carcinogenesis. In addition, the safety assessment of Aconitum Carmichael Debx., Triptervgium wilfordii Hook. f. and Polvgonum multiflora Thunb. as well as their detoxification methods were still a hot issue. Therefore, study on the toxicity mechanism of TM targeting organs, processing and extract methods, quality control, and dose control, new models and methods should be used in the prevention of TM toxicology in the future.
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