JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Kun Ren,Xuanmeng Zhang,Ruijie Wang,Shumeng Ren,Huiming Hua,Dongmei Wang,Yingni Pan,Xiaoqiu Liu
Ethnopharmacological relevance Euodiae Fructus (EF), the dried, unripe, scented fruit of Tetradium ruticarpum (A. Juss, T.G.Hartley), is a traditional food and herb with mild toxicity. In Asia, it is processed with licorice (EFP), which has been used for centuries to alleviate pain and suppress cough. Pharmacological studies have reported that this herb could cause liver injury by activating the P450 3A enzyme, thus carrying the risk of clinical application. Processing with licorice is an effective method to reduce EF toxicity. It is urgent to explore the toxic components of EF and the attenuation mechanism of licorice. Aim of the study This study aimed to indicate the specific pathway of EF-induced damage and identify the mechanism of action of licorice in reducing P450 activation and resulting in reduced liver damage. Materials and methods Male C57BL-6 mice were used to investigate the toxicity of EF to the liver and determine the attenuation effect on P450 from licorice ingestion. Glutathione (GSH) was used to capture the metabolic activation intermediates of EF. The key component reducing the EF toxicity of licorice was investigated by comparing the differences in chemical components and inhibition on the EF metabolism of licorice from different habitats. Results The intermediate product of evodiamine (EVO) in EF was found to be activated by the P450 enzyme during metabolism, causing liver injury and inflammation. Isoliquiritigenin and liquiritigenin in licorice produced by intestinal bacterial metabolism and glycyrrhizin inhibited the metabolic activation of EF. Glycosides in licorice are metabolized into aglycones by intestinal bacteria , inhibiting the metabolic activation of EF and alleviating hepatotoxicity. Conclusions By combining with GSH, the electrophilic intermediates produced by the P450 enzyme's metabolic activation of the indole ring of EVO might cause hepatotoxicity. Glycyrrhizin from licorice and the liquiritigenin and isoliquiritigenin generated by intestinal bacterial metabolism play an attenuated function by inhibiting the P450 enzyme and preventing the metabolic activation of EF.
研究领域:
药理学
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毒理学
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中医药学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF TOXICOLOGICAL SCIENCES
·
2014
·Vol. 39
·期 4
·609-614
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IF 1.378
Xiao Run-mei,Wang Jun-jun,Chen Jing-ya,Sun Li-juan,Chen Yong
Betel-quid use is associated with the risk of liver cirrhosis and hepatocellular carcinoma. The aim of the present work was to evaluate the impact of arecoline on human hepatic cytochrome P450 (CYP) enzymes in vitro and rat hepatic CYP enzymes, as well as the hepatic oxidative stress and liver injury of rats in vivo. The in vitro results indicated that arecoline hydrobromide (AH) has no significant effect on the activities of CYP2B, 2C9, 3A4, 1A2, 2E1 and 2D6 in human liver microsome (HLM). However, oral administration of AH at 4 and 20 mg/kg/d for seven consecutive days significantly increased the activities of rat hepatic CYP2B, 2E1, 2D, 3A, 2C and 1A2. In addition, AH at 100 mg/kg/d significantly increased the levels of ALT, AST and MDA, decreased the levels of SOD, CAT, GSH-Px and GSH, in rat liver. The in vivo induction of AH on rat hepatic CYP isoforms suggested that the high risk of metabolic interaction should be existed when the substrate drugs of the six kinds of CYP isoforms was administered in betel-quid use human. Furthermore, the in vivo results also suggested that AH-induced hepatoxicity should be associated with the induction of AH on rat hepatic CYP2E1 and 2B.
研究领域:
药理学
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毒理学
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肝脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2018
·Vol. 19
·期 7
·2140
·
IF 3.687
Huaqiao Tang,Min Xu,Fei Shi,Gang Ye,Cheng Lv,Jie Luo,Ling Zhao,Yinglun Li
Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals.Keywords:nano-copper;oral exposure;liver toxicity;CYP450 enzymes;mechanism
研究领域:
毒理学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 39
·期 6
·e70093
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IF 1.7
Longxin Guo,Li Lin,Jun Ling,Shengkai Zhu,Xinyu Li,Minjuan Long,Yingjie Xu,Zhanjiang Hu,Ming Niu,Xu Zhao,Xiaohe Xiao
Corydalis yanhusuo W.T.Wang (YHS) is a commonly used traditional Chinese medicine, often prescribed for treating a variety of pains. In recent years, there has been a gradual increase in the number of reports to liver injury caused by YHS and its preparations, but the exact type and mechanism of hepatotoxicity are still unclear. In the present study, we demonstrated that YHS could induce idiosyncratic drug-induced liver injury (IDILI) in the inflammatory activation models. A total of 459 differential genes and 25 differential metabolites were identified by transcriptomics and metabolomics, which were significantly enriched in the TNF and NF-κB signaling pathways as well as glycerophospholipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism. In addition, YHS significantly increased the levels of TNF-α, IL-1β, and IL-6. Therefore, we believe that the mechanism of toxicity may be related to the TNF and NF-κB signaling pathways, with glycerophospholipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism also playing important roles. It provides a reference for the safe and rational use of YHS in clinical practice and contributes to the precise prevention and control of the risk of liver toxicity associated with YHS.
研究领域:
中药学
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毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
·
IF 6.8
Jing Xiang,Hao Wu,Jinwei Gao,Weimin Jiang,Xing Tian,Zhonggui Xie,Tao Zhang,Jia Feng,Rui Song
Niclosamide (NIC) is the only commercially available molluscicide for controlling schistosomiasis, and its negative effects on aquatic animals had been frequently reported in recent years. However, the toxicity mechanism of NIC on the Chinese soft-shelled turtle ( Pelodiscus sinensis ) have not yet been investigated. Therefore, juvenile turtles were exposed to 0 (control group), 10 (low NIC, L), and 50 (high NIC, H) μg/L NIC for 120 h and our results demonstrated that NIC exposure induced severe pathological changes in the liver of P. sinensis . And the typical symptom included edema, nuclear migration and deformation, and vacuolization. Compared with the liver, the NIC exposure did not cause significant damage in the gut tissue. In addition, the DHE staining demonstrated that the ROS production of liver and gut increased with the increase in concentration of NIC. The activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) was inhibited with increased malondialdehyde (MDA) content, indicating that the antioxidant defense was significantly perturbed. Further, the transcriptome sequencing and was applied to evaluate the underlying toxicity mechanisms of NIC exposure in liver and gut of P. sinensis . Pathway enrichment showed that the disorder of lipid metabolism and innate immune regulation, including Toll-like receptors (TLRs), tumor necrosis factor (TNF), lectins, and complement and coagulation cascades, were toxicological properties of NIC on P. sinensis . Overall, the current study provides valuable information to understand the toxic effect of NIC on Chinese soft-shelled turtle.
研究领域:
环境毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
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2023
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IF 5.8
Zhang Shuwen,Luo Ting,Weng You,Wang Dou,Sun Li,Yu Zheping,Zhao Yao,Liang Senmiao,Ren Haiying,Zheng Xiliang,Jin Yuanxiang,Qi Xingjiang
Carbendazim (CBZ) and prochloraz (PCZ) are broad-spectrum fungicides used in agricultural peat control. Both fungicides leave large amounts of residues in fruits and are toxic to non-target organisms. However, the combined toxicity of the fungicides to non-target organisms is still unknown. Therefore, we characterized the toxic effects of dietary supplementation with CBZ, PCZ, and their combination for 90 days in 6-week-old male Institute of Cancer Research (ICR) mice. CBZ-H (100 mg/kg day), PCZ-H (10 mg/kg day), and their combination treatments increased the relative liver weights and caused liver injury. The serum total cholesterol (TC), triglyceride (TG), glucose (Glu), pyruvate (PYR), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were reduced, and synergistic toxicity was observed. Hepatic transcriptome revealed that 326 differentially expressed genes (DEGs) of liver were observed in the CBZ treatment group, 149 DEGs in the PCZ treatment group, and 272 DEGs in the combination treatment group. According to KEGG enrichment analysis, the fungicides and their combination affected lipid metabolism, amino acid metabolism, and ferroptosis. In addition, the relative mRNA levels of key genes involved in lipid metabolism were also examined. Compared with individual exposure, combined exposure to CBZ and PCZ caused a more obvious decrease in the expression of some genes related to glycolipid metabolism. Furthermore, the relative mRNA levels of some key genes in the combination treatment group were lower than those in the CBZ and PCZ treated groups. In summary, CBZ, PCZ, and their combination generally caused hepatotoxicity and glycolipid metabolism disorders, which could provide new insights for investigating the combined toxicity of multiple fungicides to animals.
研究领域:
毒理学
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分子生物学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENT INTERNATIONAL
·
2025
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IF 9.7
Mingshu Li,Fuchang Deng,Li Dong,Xiaona Wang,Haiyan Jiang,Siyu Yao,Yuanyuan Chen,Lian Duan,Huamao Du,Guangqiu Qin,Song Tang
Aluminum oxide (Al 2 O 3 ) nanoparticles (NPs) are extensively utilized in the food industry for applications such as food packaging, antimicrobial coatings, food processing equipment, and additives. Despite their widespread use, the mechanisms underlying Al 2 O 3 NP-induced hepatotoxicity and the relationship between their physicochemical properties and toxicity remain inadequately understood. In this study, we explored the hepatotoxic effects of α -Al 2 O 3 and γ -Al 2 O 3 NPs in rats subjected to oral exposure for 28 days. Employing an integrated metabolomics and microbiome approach, we aimed to elucidate the potential mechanisms involved. Our findings revealed distinct hepatotoxic profiles for α -Al 2 O 3 and γ -Al 2 O 3 NPs, potentially mediated by differential interactions with the intestinal microbiome. α -Al 2 O 3 NPs exhibited reduced hepatotoxicity, as evidenced by minimal liver oxidative stress, which may be associated with the upregulation of digestion-related intestinal flora such as Peptococcaceae and Romboutsia , potentially influencing Al 2 O 3 accumulation in the liver. Conversely, γ -Al 2 O 3 NPs demonstrated pronounced hepatotoxicity, characterized by liver histopathological changes and elevated levels of alanine aminotransferase, malondialdehyde, and glutathione. This increased toxicity was correlated with alterations in intestinal flora, including Ruminococcaceae and Exiguobacterium , which affected metabolites like L-phenylalanine and arachidonic acid, potentially contributing to hepatotoxicity. The results underscore the importance of the intestinal microbiome in mediating NP-induced toxicity and determining differences in toxicities of different NP phases. This study provides valuable insights into the differential toxicological impacts of Al 2 O 3 NP phases, paving the way for safer nanomaterial design and application in the food industry.
研究领域:
毒理学
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纳米生物学
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食品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Mingyang Chen,Yaodong Yi,Binxin Chen,Hengbin Zhang,Minlei Dong,Luexiang Yuan,Hui Zhou,Huidi Jiang,Zhiyuan Ma
Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1–100 μM) inhibited DOX (500 nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500 mg/kg or by gavage at 50, 100, or 200 mg/kg reduced DOX (8 mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.
研究领域:
药理学
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毒理学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2023
·
IF 9.8
Yu Han,Hongmei Yang,Zhiqun Liu,Chao Hu,Imane Lamine,Zhiquan Liu,Panpan Gao,Yanming Sui,Pei Zheng,Hangjun Zhang,Xiuying Jia
Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) have been widely used as flame retardants. However, their potential health risks to organisms have raised concerns, particularly for liver toxicity. Present study aimed to explore the toxic effects of TCBPA and TBBPA on black-spotted frogs ( Pelophylax nigromaculatus ) liver oxidative stress, autophagy, and lipid accumulation. After exposure to 0.001, 0.01, 0.1, and 1 mg/L TBBPA and TCBPA for 14 days, the content of cholesterol and triglyceride were significantly elevated. In addition, the malondialdehyde level rose greatly in dose dependent. However, the glutathione level declined in high TBBPA groups (0.01 and 0.1 mg/L). Furthermore, expressions of Beclin1 , Atg5 , and Atg7 were significantly increased, while p62 was markedly declined, respectively. Results obstained suggested that TBBPA and TCBPA exposure induced liver toxicity in black-spotted frog. This study provided insights into the toxicity mechanism of bisphenol flame retardants in amphibians and will aid in the ecological risk assessment of flame retardants.
研究领域:
环境毒理学
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水生生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Hao Zhang,Jia-Gen Cui,Ming-Shan Chen,Jia-Xin Wang,Xiao-Han Sun,Yi Zhao,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.
研究领域:
毒理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
·
IF 12.2
Yue Zhang,Hongmin Lu,Lulu Hou,Xin Zhang,Tiantian Guo,Ruoqi Wang,Qi Wang,Mingwei Xing
Acetochlor is a widely used and highly effective herbicide. Its overuse poses significant threats to biosecurity and ecological integrity, particularly affecting free-ranging birds. Data on its impact, especially mechanisms of liver toxicity in chickens, are lacking. Thus, we established an animal-cell-animal model to explore intrinsic mechanisms at multiple levels. We found that acetochlor exposure caused liver cell swelling, inflammatory cell accumulation, and lipid deposition. Transcriptomic analyses revealed that differential gene were mainly enriched in hepatic immune, inflammatory, and programmed cell death pathways. We next focused on the gene GPR120, conducting transfection and agonism experiments in LMH, HD11, and co-cultured cells. Acetochlor significantly increased ROS accumulation, activated the NLRP3 inflammasome, and which induced PANoptosis. HD11 cells exhibited M1 polarization with upregulated pro-inflammatory factors. Silencing GPR120 exacerbated cellular damage and immune responses, whereas its agonist, GSK7A, dramatically reduced macrophage M1 polarization and mitigated immune damage to LMH cells. Finally, we returned to animal studies, adding Omega-3-a known GPR120 agonist-to the diet. Omega-3 effectively reversed acetochlor-induced hepatitis and PANoptosis. Given that acetochlor residues pose potential threats to ecosystems and avian health, it is crucial to strengthen residue control, conduct risk assessments, and explore targeted pathways and nutritional supplementation to counteract these negative impacts.
研究领域:
毒理学
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免疫学
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分子生物学
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兽医学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY
·
2013
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IF 4.017
Meijuan Tu,Siyuan Sun,Kai Wang,Xueying Peng,Ruihan Wang,Liping Li,Su Zeng,Hui Zhou,Huidi Jiang
Monocrotaline (MCT) is a kind of toxic retronecine-type pyrrolizidine alkaloids (PAs) from plants of Crotalaria , which can be bio-activated by cytochrome P450 (CYP) enzymes in liver and then induce hepatotoxicity. Since CYPs are localized in the endoplasmic reticulum , the influx of MCT to the liver is the key step for its hepatotoxicity. The objective of the present study was to investigate the role of organic cation transporter 1 (OCT1), a transporter mainly expressed in liver, in the uptake of MCT and in hepatotoxicity induced by MCT. The results revealed that MCT markedly inhibited the uptake of 1-methyl-4-phenylpyridinium (MPP + ), an OCT1 substrate, in Madin–Darby canine kidney (MDCK) cells stably expressing human OCT1 (MDCK-hOCT1) with the IC 50 of 5.52 ± 0.56 μM. The uptake of MCT was significantly higher in MDCK-hOCT1 cells than in MDCK-mock cells, and MCT uptake in MDCK-hOCT1 cells followed Michaelis–Menten kinetics with the K m and V max values of 25.0 ± 6.7 μM and 266 ± 64 pmol/mg protein/min, respectively. Moreover, the OCT1 inhibitors, such as quinidine , d -tetrahydropalmatine ( d -THP), obviously inhibited the uptake of MCT in MDCK-hOCT1 cells and isolated rat primary hepatocytes, and attenuated the viability reduction and LDH release of the primary cultured rat hepatocytes caused by MCT. In conclusion, OCT1 mediates the hepatic uptake of MCT and may play an important role in MCT induced-hepatotoxicity.
研究领域:
毒理学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）