Toxicology letters最新文献

{"title":"The herbicide 2,4-dichlorophenoxyacetic acid induces pancreatic β-cell death via oxidative stress-activated AMPKα signal downstream-regulated apoptotic pathway","authors":"Ken-An Lin ,&nbsp;Chin-Chuan Su ,&nbsp;Kuan-I Lee ,&nbsp;Shing-Hwa Liu ,&nbsp;Kai-Min Fang ,&nbsp;Chih-Hsin Tang ,&nbsp;Wei-Cheng Lia ,&nbsp;Chun-Ying Kuo ,&nbsp;Kai-Chih Chang ,&nbsp;Chun-Fa Huang ,&nbsp;Ya-Wen Chen ,&nbsp;Ching-Yao Yang","doi":"10.1016/j.toxlet.2025.01.009","DOIUrl":"10.1016/j.toxlet.2025.01.009","url":null,"abstract":"<div><div>2,4-Dichlorophenoxyacetic acid (2,4-D) is one of commonly and widely used organic herbicides in agriculture. It has been reported that 2,4-D can induce adverse effects in mammalian cells. Epidemiological and animal studies have indicated that exposure to 2,4-D is associated with poorer glycemic control and impaired pancreatic β-cell function. However, limited information is available on 2,4-D-induced toxicological effects in β-cells, with the underlying toxicological mechanisms remains unclear. Herein, our results showed that 2,4-D exposure (30–500 μg/mL) significantly reduced cell viability, induced mitochondria dysfunction (including the mitochondrial membrane potential (MMP) loss, the increase in cytosolic cytochrome c release, and the change in Bcl-2 and Bax protein expression), and triggered apoptotic events (including the increased population of apoptotic cells, caspase-3 activity, and caspase-3/-7 and PAPR activation) in RIN-m5F β-cells, accompanied with insulin secretion inhibition. Exposure of cells to 2,4-D could also evoke JNK, ERK1/2, p38, and AMP-activated protein kinase (AMPK)α activation as well as reactive oxygen species (ROS) generation. Pretreatment of cells with compound C (an AMPK inhibitor) and the antioxidant<em>N</em>-acetylcysteine (NAC), but not that SP600125/PD98059/SB203580 (the inhibitors of JNK/ERK/p38, respectively), obviously attenuated the 2,4-D-triggered AMPKα phosphorylation, MMP loss, apoptotic events, and insulin secretion dysfunction,as similar effects with the transfection with AMPKα1-specific siRNA. Of note, buffering the ROS production with NAC obviously prevented the 2,4-D-induced ROS generation as well as AMPKα activation, but the either compound C and AMPKα1-specific siRNA transfection could not effectively reduce 2,4-D-induced ROS generation. Collectively, these findings indicate that the induction of oxidative stress-activated AMPKα signaling is a crucial mechanism underlying 2,4-D-triggered mitochondria-dependent apoptosis, ultimately leading to β-cell death.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"405 ","pages":"Pages 16-29"},"PeriodicalIF":2.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigation of gentamycin induced acute kidney injury due to benzothiazole derivatives N1 and N5: Antioxidant and renoprotective mechanisms in-vivo zebrafish","authors":"S. Madesh ,&nbsp;Senthilkumar Palaniappan ,&nbsp;Anand Aravind ,&nbsp;Avra Sau ,&nbsp;Mikhlid H. Almutairi ,&nbsp;Bader O. Almutairi ,&nbsp;Ilavenil Soundharrajan ,&nbsp;S. Karthick Raja Namasivayam ,&nbsp;Kathiravan Muthu Kumaradoss ,&nbsp;Jesu Arockiaraj","doi":"10.1016/j.toxlet.2025.02.001","DOIUrl":"10.1016/j.toxlet.2025.02.001","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is marked by a rapid decline in renal function, often caused by oxidative stress and nephrotoxic agents. Complications limit current therapeutic strategies, and no specific drugs are available to prevent renal injury or accelerate recovery. In the present research, we investigated the therapeutic efficacy of synthesized 2-aminobenzothiazole derivatives, N1 and N5, in mitigating Gentamicin (Gen) -induced renal damage <em>in vivo</em> zebrafish. The preliminary work of radical scavenging and hemolysis inhibition assay revealed that, both compounds exhibited strong antioxidant and anti-inflammatory activities. Furthermore, acute toxicity assays in zebrafish embryo/larvae revealed no adverse effects at concentrations up to 200 μM were tested, highlighting the safety of these compounds. In the zebrafish AKI model, Gen exposure led to oxidative stress, inflammation, and impaired glomerular filtration with tissue damage. Treatment with N1 and N5 significantly reduced ROS levels, apoptosis, and lipid peroxidation and restored antioxidant enzyme activities. Furthermore, N5 treatment improved renal filtration and reduced proteinuria levels, indicating its ability to mitigate nephrotoxic effects. Gene expression analysis showed that N1 and N5 downregulated pro-inflammatory markers (<em>cox-2</em>, <em>tnfα</em>, <em>mpo</em>) and angiogenic mediators (<em>vegf</em>, <em>vegfr2</em>), demonstrating anti-inflammatory and anti-angiogenic properties. Histological analyses revealed that N1 and N5 attenuated glomerular and tubular damage, reduced necrosis, and promoted tissue repair. These findings highlight the potential of 2-aminothiazole derivatives as effective therapeutic agents for AKI, offering antioxidant, anti-inflammatory, and cytoprotective benefits and warranting further investigation into their long-term efficacy in chronic kidney disease models.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"405 ","pages":"Pages 30-40"},"PeriodicalIF":2.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional profiling of exosomes derived from serum of patients with rare earth pneumoconiosis by RNA-sequencing and PI3K/Akt pathway is activated in lung of mice exposed to rare earth Nd2O3","authors":"Yanrong Gao ,&nbsp;Shurui Wang ,&nbsp;Yuanqi He ,&nbsp;Yupeng Ma ,&nbsp;Suhua Wang","doi":"10.1016/j.toxlet.2025.01.001","DOIUrl":"10.1016/j.toxlet.2025.01.001","url":null,"abstract":"<div><div>Rare earth is used extensively around the world, and rare earth particles cause a respiratory disease in workers termed rare earth pneumoconiosis(REP) that have attracted considerable attention. However, the mechanisms of REP, characterized by diffuse pulmonary fibrosis, are elusive. REP progression involves various signaling pathway networks comprising numerous cell types and cytokines. Acting as an important medium for communication between cells, exosomes are emerging as a major research topic. However, the role of exosomal lncRNAs, miRNAs and mRNAs in REP remains unclear. In the present study, we conducted high-throughput RNA sequencing to generate long non-coding RNA(lncRNA), microRNA (miRNA) and mRNA profiles from the serum exosomes of nine patients with rare earth pneumoconiosis and nine healthy people. Our results identified a total of 94 lncRNAs, 93miRNAs, and 29 mRNAs were differentially expressed in the serum exosomes of patients with rare earth pneumoconiosis. Subsequently, Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to analyze the differentially expressed RNAs. The abundant enriched GO terms of exosomal genes are cytoplasm, protein binding, cytoskeleton, Nuclear cytoplasmic transport, and KEGG pathways of exosomal genes included metabolic and cancer pathway, PI3K/Akt, wnt, mTOR, HIF-1, actin cytoskeleton and cell cycle and so on. RT-qPCR results showed that lnc-KCNMB2-AS1, hsa-miR-186–5p, hsa-miR-100–5p, hsa-miR-381–5p, NCOA4 and PLXDC1 were up-regulated, and lnc-TMEM151A, hsa-miR-758–5p and hsa-miR-6842–5p were significantly down-regulated in exosomes. In addition, our study fuond that the PI3K/Akt pathway was activated, and the expression level of miR-100–5p was increased synchronously in lung tissue of mice exposed to rare earth Nd₂O₃. In this study, PI3K/Akt pathway is significant helpful in elucidating the mechanism of REP. These findings can provide new insights into the mechanism of REP and develop a novel treatment strategy and biomarker.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 9-19"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Review of the genotoxicity of \"Arvin compounds\", drinking water contaminants formed by the degradation of antioxidants in polyolefin pipes” [Toxicol. Lett. 402 (2024) 81–90]","authors":"Wolfgang Dekant","doi":"10.1016/j.toxlet.2025.01.006","DOIUrl":"10.1016/j.toxlet.2025.01.006","url":null,"abstract":"","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Page 67"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple acetylcholinesterase inhibition assay for the quantification of the nerve agent VX: Application in a Franz cell model with rat skin and various decontaminants","authors":"Amelie Schwab ,&nbsp;Gabriele Horn ,&nbsp;Kai Kehe ,&nbsp;Franz Worek ,&nbsp;Niko Amend","doi":"10.1016/j.toxlet.2025.01.002","DOIUrl":"10.1016/j.toxlet.2025.01.002","url":null,"abstract":"<div><div>The medical community continues to regard organophosphate nerve agent poisoning as a significant concern. Due to the lack of therapeutic options for the nicotinic signs and symptoms for certain agents (e.g. tabun), decontamination remains a pivotal aspect of patient care. Current models to study skin penetration of nerve agents and the respective decontamination rely on expensive, laborious and not readily available methods, i.e. GC-MS-MS and LC-MS-MS. Hence, we used a photometric acetylcholinesterase (AChE) inhibition assay for the quantification of nerve agents, relying on VX as a model substance. Inhibition curves were determined in a time dependent manner and consecutively slopes of the tangents and the calculated standard curve were used for quantification. The concentration dependent rate constant of VX with human AChE (<em>k</em>_<em>1</em>) and the inhibitor concentration [IX] were used to plot 1/<em>k</em>_<em>1</em> against 1/[IX]-(1-<em>α</em>). <em>α</em> equals [S]/(<em>K</em>_<em>m</em>+[S]), [S] being the substrate and K_m the Michaelis-Menten-constant. A Franz cell model served as an example to determine the robustness and suitability of the assay to study penetration rates and the success of decontamination. The inhibition assay delivers robust results, even when the decontamination protocol interferes with the colorimetric Ellman assay. Hence, we provide a generic, low-cost method for the quantification of nerve agents in a model studying the decontamination of nerve agents.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 20-27"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of mitochondrial dysfunction and oxidative stress in the nephrotoxicity induced by high-fat diet in Sprague-Dawley rats","authors":"Bin Zhang,&nbsp;Jianfang Xu,&nbsp;Mengdie Wang,&nbsp;Chang Yu","doi":"10.1016/j.toxlet.2025.01.004","DOIUrl":"10.1016/j.toxlet.2025.01.004","url":null,"abstract":"<div><div>The prevalence of obesity-associated kidney injury has increased, yet the precise extent of the injury and its underlying mechanisms remain unclear. This study used a Sprague-Dawley (SD) rat model to simulate human exposure scenarios, with the objective of investigating the involvement of mitochondria in obesity-induced renal toxicity. Biochemical analysis revealed significant increases in serum creatinine, cystatin C, urinary protein, urinary microalbumin, and urinary α1-microglobulin levels in rats fed a high-fat diet, indicating a notable decline in glomerular filtration function. Histopathological examination showed mild to moderate degeneration in renal tubular epithelial cells, slight glomerular enlargement, fusion and disappearance of pedunculated cell, and decreased electron density of mitochondrial matrix and cristae, indicating the impaired filtration function of kidney. Furthermore, the study found reduced mitochondrial membrane potential and superoxide dismutase (SOD) levels, along with increased malondialdehyde (MDA) levels, signifying elevated mitochondrial oxidative stress in the kidneys of high-fat diet-fed rats. Additionally, a decrease in the number of mitochondrial uncoupling protein-2 (UCP-2) and proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-positive cells, as well as reduced protein expression levels in the mitochondria, suggests a reduced renal mitochondrial resistance to oxidative stress. Collectively, these findings indicate that a high-fat diet triggers abnormalities in both renal filtration and structural functionality in SD rats. The observed reduction in renal mitochondrial density and the elevation in oxidative stress levels could potentially serve as underlying mechanisms.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 28-36"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of occupational aluminum exposure on blood pressure and blood glucose in workers – A longitudinal study in northern China","authors":"Lingshan Xue ,&nbsp;Shihui Guo ,&nbsp;Jiaping Huan ,&nbsp;Chenyang Li ,&nbsp;Jing Song ,&nbsp;Linping Wang ,&nbsp;Huifang Zhang ,&nbsp;Baolong Pan ,&nbsp;Qiao Niu ,&nbsp;Xiaoting Lu ,&nbsp;Jinzhu Yin","doi":"10.1016/j.toxlet.2025.01.005","DOIUrl":"10.1016/j.toxlet.2025.01.005","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Trace element and metal exposure is closely related to the occurrence of chronic diseases, particularly affecting blood pressure and blood glucose. Current studies suggest that heavy metal exposure is a risk factor for hypertension and diabetes. Aluminum can enter the human body through daily life and occupational exposure from food, environment, drugs, and other sources, affecting the cardiovascular, endocrine, and other systems. Therefore, it is significant to observe the effect of aluminum on blood pressure and blood glucose in workers with high concentration.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;In this study, electrolytic workers naturally exposed to high concentrations of aluminum were selected. The aim of the 5-year cohort study was to investigate the effects of continuous occupational aluminum exposure on blood pressure and blood glucose in workers and to assess the risk of potential cardiovascular and metabolic diseases due to heavy metal exposure.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;In 2014, 183 participants from an electrolysis workshop at an aluminum plant in Shanxi were enrolled. Inductively coupled plasma mass spectrometry (ICP-MS) was performed to determine the plasma aluminum (P-Al) concentration of the workers and measured their blood pressure and glucose levels. At the 2019 follow-up, all parameters were measured again in the same workers. The relationship of the P-Al concentration with blood pressure and glucose levels was assessed using generalized linear regression, and risks of developing hypertension and hyperglycemia (diabetes or pre-diabetes) due to Al exposure were assessed using binary logistic regression. Dose-response relationships between average annual rates of change in P-Al and average annual rates of change in blood pressure and blood glucose were analyzed using RCS. The relative risk (RR) and attributable risk (AR) were also calculated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Generalized linear regression showed that the average annual rate of change in P-Al concentration was positively correlated with the annual rates of change in SBP, DBP, and blood glucose levels, with each e-fold increase in P-Al concentration increasing the annual rates of change in SBP and DBP by 3.55 % (&lt;em&gt;P&lt;/em&gt; &lt; 0.01) and 3.43 % (&lt;em&gt;P&lt;/em&gt; = 0.03), respectively. Binary logistic regression showed that as the average annual rate of change in P-Al concentration (categorical variable) increased, the risk of developing hypertension increased (P&lt;sub&gt;trend&lt;/sub&gt; &lt; 0.05). The RCS results showed that the relationship between the average annual rate of change in P-Al and the average annual rate of change in SBP was a showed a dose-response relationship (&lt;em&gt;P&lt;/em&gt; for overall association&lt;0.05). RR and AR increased with increasing P-Al concentration in both hypertensive and diabetic patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Persistent occupational aluminum exposure is associated with elevated blood ","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 47-57"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding of ligands to the aryl hydrocarbon receptor: An overview of methods","authors":"Jiří Hrubý,&nbsp;Zdeněk Dvořák","doi":"10.1016/j.toxlet.2025.01.003","DOIUrl":"10.1016/j.toxlet.2025.01.003","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays numerous and pivotal roles in human physiology and pathophysiology. Therefore, pharmacotherapeutic targeting of the AhR is a highly pertinent issue. The identification of new AhR ligands and the characterization of the interactions between the AhR ligands and AhR protein requires appropriate methodology. In spite the AhR is monomeric intracellular soluble receptor, the full-length human AhR protein has not been crystallized so far, and its isolation in a form applicable in the binding assays is highly challenging. Recent advances, including crystallization of AhR fragments, recombinant protein technologies, and cryogenic electron microscopy, allowed for exploitation of diverse experimental techniques for studying interactions between ligands and the AhR. In the current paper, we review existing AhR ligand binding assays, including their description, applicability and limitations.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 37-46"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging nicotine analog 6-methyl nicotine increases reactive oxygen species in aerosols and cytotoxicity in human bronchial epithelial cells","authors":"Felix Effah ,&nbsp;Yehao Sun ,&nbsp;Alan Friedman ,&nbsp;Irfan Rahman","doi":"10.1016/j.toxlet.2025.01.007","DOIUrl":"10.1016/j.toxlet.2025.01.007","url":null,"abstract":"<div><div>Nicotine-contained e-cigarettes (E-cigs) generate reactive oxygen species (ROS), volatile organic compounds, and heavy metals. Inhalation toxicology studies suggest that exposure to these toxicants may adversely impact human health. These findings led to the U.S. Food and Drug Administration’s (FDA) regulation of nicotine-containing E-cigs under the Tobacco Regulation Act (TRA) of 2020. Manufacturers aiming to sell nicotine products in the U.S. must submit a Premarket Tobacco Product Application (PMTA) and obtain FDA approval before marketing their products. However, due to the lengthy PMTA process, some companies have exploited a loophole in the TRA (2020) by introducing nicotine analogs, such as 6-methyl nicotine (6-MN) into E-cig products. 6-MN is marketed as a ‘safer’ alternative to nicotine, offering comparable satisfaction despite not being derived from tobacco or nicotine. Nonetheless, its safety profiles are unknown. Therefore, this study tested the toxicity of 6-MN compared to traditional nicotine <em>in vitro</em>. We observed that thermal degradation of 6-MN in e-liquids significantly generated more ROS in the aerosols than nicotine. We investigated the dose-response cytotoxicity of 6-MN vs nicotine when exposed to HBEC3-KT human bronchial epithelial cells. 6-MN-contained e-liquids significantly increased cytotoxicity and intracellular ROS induction in a dose-specific manner compared to nicotine. Further, we observed that 6-MN (pure compound) transiently increased metabolic activity significantly at all doses tested compared to nicotine. Given the potential risks associated with 6-MN, it cannot be deemed ‘safer’ than nicotine. Therefore, further primary toxicological research is urgently needed to provide regulatory agencies with more robust data to implement regulations.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"405 ","pages":"Pages 9-15"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic activation and hepatic cytotoxicity of osthole mediated by cytochrome P450 enzymes","authors":"Siyu Liu ,&nbsp;Guode Zhao ,&nbsp;Yingyun Xu ,&nbsp;Yang Wang ,&nbsp;Zifang Ding ,&nbsp;Weiwei Li ,&nbsp;Ying Peng ,&nbsp;Jiang Zheng","doi":"10.1016/j.toxlet.2024.12.009","DOIUrl":"10.1016/j.toxlet.2024.12.009","url":null,"abstract":"<div><div>Osthole (OST), a coumarin derivative, is one of the major components of <em>Cnidium monnieri</em> (L.) Cussion. OST was reported to induce apoptosis in hepatocytes. Elevated serum ALT and AST were documented in Sprague-Dawley rats after administration of OST. In the present study, OST was found to be metabolized to a phenol metabolite which was further metabolically oxidized to the corresponding quinone methide intermediate. A glutathione conjugate derived from the reactive metabolite was detected <em>in vitro</em> and <em>in vivo</em>. The structures of the metabolites were verified by chemical analysis. CYP3A4 and CYP1A2 were the major enzymes to catalyze the oxidation reactions. Pre-treatment with 1-aminobenzotriazole or ketoconazole decreased the susceptibility of primary hepatocytes to the cytotoxicity of OST. The findings provided solid evidence that the metabolic activation of OST correlated with the cytotoxicity of OST.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"404 ","pages":"Pages 1-8"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}