Toxicology letters最新文献

{"title":"Adduct of the plant protein RuBisCO formed upon interaction with G-type organophosphorus nerve agents","authors":"Qian Wang ,&nbsp;Meng Jin ,&nbsp;Hongmei Wang ,&nbsp;Xiaogang Lu ,&nbsp;Runli Gao ,&nbsp;Fengxia Sun","doi":"10.1016/j.toxlet.2025.05.013","DOIUrl":"10.1016/j.toxlet.2025.05.013","url":null,"abstract":"<div><div>The Chemical Weapons Prohibition Convention (CWC) explicitly prohibits the use of organophosphorus nerve agents (OPNAs), which are highly toxic cholinesterase inhibitors that pose a serious threat to human peace, health and security. Currently, protein adducts of OPNAs are mainly studied in humans and animals. However, a novel and reliable biomarker must be found immediately to provide retrospective identification of OPNA exposure in environmental samples. In this study, we aimed to broaden the detection window for nerve agents in various species, explore prospective biomarkers for their high reactivity and good stability, and examine the feasibility of adding plant proteins to G-type OPNAs. We investigated the plant protein ribulose-1,5-diphosphate carboxylated oxygenase (RuBisCO). Several modification sites were discovered, including S115/S117 and Y118/Y120 on EHHNS*PGY*Y*DGR and K175 on Y*GRPLLGCTIK*PK. Ten reliable and stable peptide segments were also identified. Both tabun (GA) and soman (GD) can concurrently modify the peptides EHHNS*PGY*Y*DGR, WS*PELAAACEVWK* , Y*GRPLLGCTIK*PK, and GHYLNATAGTCEDMMK. As a result, the exposure to OPNAs can be retrospectively verified using these stabilized peptides. The stability of the three OPNA adducts varies. The sarin (GB) adduct is the most stable, while GA-Lys and GA-Ser show the fastest aging rate, followed by GD. The differential aging rates of OPNA adducts may provide temporal clues for distinguishing exposure sources, provided that aging kinetics are validated <em>in vivo</em> and under specified post-exposure timeframes. This study proposes a novel method for retrospective organophosphorus analysis, with potential applications in forensic investigations and chemical weapon verification. A computer-based molecular simulation of the highly reactive stable modification sites revealed that hydrogen bonds are the driving force for the formation of covalent compounds. This study contributes to our understanding of the mechanism of modification site formation of the RuBisCO adduct.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"410 ","pages":"Pages 32-38"},"PeriodicalIF":2.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168885","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":"Extracellular vesicles from tomatoes upregulate CYP1A1 mRNA content in differentiated Caco-2 cells","authors":"Ziyu Huang ,&nbsp;Sabine Gerbal-Chaloin ,&nbsp;Martine Daujat-Chavanieu ,&nbsp;Martin Krøyer Rasmussen","doi":"10.1016/j.toxlet.2025.05.015","DOIUrl":"10.1016/j.toxlet.2025.05.015","url":null,"abstract":"<div><div>Cytochrome P450 enzymes (CYPs) from families 1–3 play a crucial role in the bioconversion and detoxification of various compounds. While the liver is a primary site for these enzymes, the small intestine also significantly contributes to first-pass metabolism. Many food-derived compounds are known to regulate CYP expression. However, it remains unclear whether plant-derived extracellular vesicles can influence CYP expression in intestinal epithelial cells. In this study, based on a previously generated transcriptomic dataset, we tested the hypothesis that tomato-derived extracellular vesicles can upregulate CYP1A1 mRNA levels in differentiated human Caco-2 cells. Further experiments confirmed that this effect is specific to differentiated Caco-2 cells and does not occur in other non-cancerous cell models or undifferentiated Caco-2 cells. The increase in CYP1A1 mRNA following treatment with extracellular vesicles was not accompanied by changes in the expression of CYP1A1-regulating transcription factors such as AhR and Sp1. In conclusion, this study is the first to demonstrate that plant-derived extracellular vesicles can affect first-pass metabolism by regulating the expression of cytochrome P450 enzymes.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"410 ","pages":"Pages 16-22"},"PeriodicalIF":2.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169000","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":"Risk assessment for the bladder carcinogenesis of 4-aminobiphenyl in smokers: A source-to-outcome study","authors":"Huanhuan Zhu ,&nbsp;Qi Xiao ,&nbsp;Huilin Zhang ,&nbsp;Meiyu Zhou ,&nbsp;Jialei Zhu ,&nbsp;Shiyao Zhang ,&nbsp;Haixia Zhu ,&nbsp;Zhengdong Zhang ,&nbsp;Haiyan Chu","doi":"10.1016/j.toxlet.2025.05.014","DOIUrl":"10.1016/j.toxlet.2025.05.014","url":null,"abstract":"<div><div>4-aminobiphenyl (4-ABP) is widely distributed in the environment and is implicated in the pathogenesis of cancer. This study aims to clarify the environmental and toxicological science of 4-ABP, which are currently unexplored. By searching articles from PubMed, Web of Science, and MEDLINE, we established an aggregate exposure pathway (AEP) framework that demonstrated the presence of 4-ABP in the cigarette smoke. Compared to nonsmokers, smokers had relatively higher levels of 4-ABP and its adducts in blood, urine, and bladder tissues. Then, an adverse outcome pathway (AOP) was constructed using bioinformatic tools. The AOP indicated that 4-ABP induced DNA damage, cell cycle dysregulation, and angiogenesis in the development of bladder cancer. <em>In vitro</em> assays confirmed that 4-ABP/cigarette smoke extract (CSE) significantly induced DNA double strand breaks and cell cycle arrest in the S phase in bladder cancer cells (J82), and 4-ABP/CSE-treated J82 cells promoted the migration and tube formation ability of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. The benchmark dose (BMD) analysis revealed that the 5th lower limit of BMD at a 5 % response (BMDL₅) derived from angiogenesis was 0.02 mM, and the corresponding human equivalent dose derived from BMDL₅ was 0.44 μg/kg/day. Our study demonstrated that 4-ABP induced bladder cancer via promoting angiogenesis in smokers, which may provide a new approach for chemical risk assessment regarding bladder carcinogenesis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"410 ","pages":"Pages 23-31"},"PeriodicalIF":2.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169001","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":"Toxicity assessment of the novel psychoactive substance HU-210 (Hebrew University 210; CAS: 112830–95-2): First insight into toxicophores and critical toxicity parameters (acute toxicity, health effects, genotoxicity, skin and eye irritation, cardiotoxicity and endocrine disruption) using in silico methods for applications in clinical and forensic toxicology","authors":"Kamil Jurowski ,&nbsp;Damian Kobylarz","doi":"10.1016/j.toxlet.2025.05.012","DOIUrl":"10.1016/j.toxlet.2025.05.012","url":null,"abstract":"<div><h3>Purpose</h3><div>For the first time, the toxicity of HU-210, a synthetic cannabinoid, has been assessed using nine different <em>in silico</em> methods, representing a novel approach in substance safety research. Given the scant data on HU-210’s human toxicological impact, our research sought to predict toxicophores and key toxicological endpoints for clinical toxicology and forensic purposes.</div></div><div><h3>Methods</h3><div>We applied nine different <em>in silico</em> predictive methods, including: StopTox, AdmetSAR 3.0, ACD/Labs Percepta, ProTox 3.0, PreADMET, ADMETlab 2.0, OCHEM, TEST and VEGA QSAR to evaluate key toxicological endpoints: acute toxicity (LD₅₀ for different species and route of exposure), genetic toxicity (Ames test), skin and eye irritation, health effects (gastrointestinal system, kidneys, liver, blood, lungs, and cardiovascular system), cardiotoxicity (hERG blocker/inhibitor and IC₅₀) and endocrine system disruption. These <em>in silico</em> methods utilized computational models and existing databases to assess HU-210’s chemical interactions and toxicological profiles across several parameters.</div></div><div><h3>Results</h3><div>Predictive analyses indicated moderate acute toxicity risks for HU-210, particularly affecting the cardiovascular, renal, and pulmonary systems. While genotoxicity appeared low, substantial concerns were raised regarding its potential to disrupt the endocrine system. Despite variances in individual software predictions, the consensus underscored significant caution regarding HU-210’s safety profile.</div></div><div><h3>Conclusions</h3><div>Our findings emphasize the need for comprehensive toxicological assessments of new psychoactive substances (NPS) like HU-210 and highlight the critical role of <em>in silico</em> studies as preliminary research tools. Although these predictions provide valuable insights for clinical toxicology (expected health effects, genotoxicity, cardiotoxicity, endocrine system disruption) and forensic toxicology (especially acute toxicity), further experimental research is crucial. Notably, toxicophore analysis identified aromatic and unsaturated moieties within the chromene core of HU-210 as structural alerts potentially associated with toxicity. Regulatory bodies should consider these potential risks, highlighting the importance of ongoing vigilance in monitoring synthetic cannabinoids—an aspect particularly crucial from a forensic toxicology perspective.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"410 ","pages":"Pages 39-57"},"PeriodicalIF":2.9,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144152048","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":"Leonurine protects against cisplatin-induced ototoxicity through its anti-oxidation and anti-apoptosis properties","authors":"Zhen Zeng ,&nbsp;Lei Han ,&nbsp;Dingding Dong ,&nbsp;Honghai Tang ,&nbsp;Ziwen Gao ,&nbsp;Shaowei Hu ,&nbsp;Biyun Zhu ,&nbsp;Sen Zhang ,&nbsp;Yilai Shu ,&nbsp;Yafeng Yu","doi":"10.1016/j.toxlet.2025.05.011","DOIUrl":"10.1016/j.toxlet.2025.05.011","url":null,"abstract":"<div><div>Cisplatin has a high efficacy for treating solid tumors, but it is generally accompanied by ototoxic side effects. Leonurine (LEO) has anti-oxidative and anti-apoptotic effects, although its role in the treatment of cisplatin-induced hearing impairment (CIHI) remains unclear. Here, we explored <em>in vitro</em> and <em>in vivo</em> models of cisplatin injury and analyzed the efficacy of LEO on cisplatin-induced ototoxicity by immunofluorescence, otoacoustic assessment, qRT-PCR, and Western blot. At the cellular level, LEO reduced oxidative stress and apoptosis, while at the organism level LEO protected guinea pigs against CIHI and maintained the hearing thresholds of cisplatin-treated guinea pigs at 50–55 dB. LEO effectively prevented cisplatin-induced decreases in hair cells, supporting cells, spiral ganglion neurons and ribbon synapses; reduced Cleaved Caspase 3 expression through activation of Bcl-2 and reducing reactive oxygen species (ROS) accumulation and improving mitochondrial membrane potential and reduced cisplatin-induced apoptosis by increasing the expression of Nrf2/Nqo1. In conclusion, the present study expands the application range of LEO and suggests that LEO is a potential therapeutic agent for preventing cisplatin ototoxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"410 ","pages":"Pages 1-15"},"PeriodicalIF":2.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142536","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":"Germline mutagenicity of molnupiravir and its active form, β-d-N4-hydroxycytidine, in Caenorhabditis elegans evaluated using whole-genome sequencing","authors":"Li Xia ,&nbsp;Jian Yan ,&nbsp;Ying Chen ,&nbsp;Timothy W. Robison ,&nbsp;Tao Chen","doi":"10.1016/j.toxlet.2025.05.007","DOIUrl":"10.1016/j.toxlet.2025.05.007","url":null,"abstract":"<div><div>Molnupiravir is a medication used to treat COVID-19 by introducing errors into the SARS-CoV-2 virus's genetic code, thereby preventing its replication. Previous studies, both <em>in vitro</em> and <em>in vivo</em>, have yielded conflicting results regarding its mutagenic potential. While most genotoxicity and mutagenicity tests for molnupiravir and its active form, β-d-N4-hydroxycytidine (NHC), were negative, a few <em>in vitro</em> tests showed positive results. Consequently, further investigation is necessary to evaluate various mutagenic endpoints of molnupiravir. In this study, acute toxicity was assessed by measuring the locomotive activity of <em>Caenorhabditis elegans</em> using a WMicroTracker to determine an appropriate dose range for the germline mutagenicity study. The <em>C. elegans</em> worms were treated with different concentrations of molnupiravir and NHC, along with vehicle controls and ethyl methanesulfonate (EMS) as a positive control. To assess germline mutagenicity, P0 worms from a single clone were exposed to selected concentrations of molnupiravir and NHC, as well as vehicle and positive controls, for 4 h. Molnupiravir and NHC treatments had no significant effect on the locomotion of <em>C. elegans</em> worms after 1-, 2-, 3-, and 4-h exposures, compared to the vehicle control group. In contrast, EMS significantly reduced the worms' locomotive activity. Subsequent whole-genome sequencing of the F1 progeny from the treated P0 worms revealed that neither molnupiravir nor NHC increased the germline mutation frequency or altered mutation types, compared to the vehicle control. In contrast, EMS treatment significantly increased mutation frequency over the vehicle control, with a EMS-specific mutational signature observed. These results suggest that molnupiravir and NHC are not mutagenic in <em>C. elegans</em> germ cells, aligning with previous findings that demonstrate the low mutagenicity of molnupiravir in clinical settings. Additionally, these findings highlight the utility of <em>C. elegans</em> as an alternative animal model for accelerating toxicity assessments and reducing the use of experimental animals.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 138-144"},"PeriodicalIF":2.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133178","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":"Self-poisoning by sodium nitrite ingestion: Investigating toxicological mechanisms in vitro","authors":"Sara Pinheiro ,&nbsp;Félix Carvalho ,&nbsp;Helena Carmo","doi":"10.1016/j.toxlet.2025.05.010","DOIUrl":"10.1016/j.toxlet.2025.05.010","url":null,"abstract":"<div><div>Nitrite ingestion has recently emerged as a suicidal method. The mechanisms of toxicity involved in fatal intoxications are associated with the disturbance of physiological processes, mainly through the massive induction of methemoglobinemia. However, there is limited information on the whole spectrum of effects following acute poisonings, requiring additional investigation. An <em>in vitro</em> study of sodium nitrite/nitrate toxicity (25–400 mM, 4 h) was conducted to assess the direct effect on cell models (H9c2, Caco-2 and SH-SY5Y). Cell viability assays (neutral red uptake and MTT reduction) were performed to obtain full concentration-toxicity curves. <em>In vitro</em> digestion assays were also conducted to study potential transformations of nitrite (2.6 g) into other chemical species within the gastrointestinal tract. Additionally, the blood levels of sodium nitrite/nitrate (1–500 mM, 20 min) associated with the increase of methemoglobin in human blood samples were evaluated using a spectrophotometric technique. Cell viability assays showed no significant toxicity of sodium nitrite or nitrate for any of the tested cell lines at biologically relevant concentrations, even those found in intoxication cases. Digestion simulation tests revealed that nitrite is likely to convert into other nitrogen species, especially in the gastric environment. <em>In vitro</em> exposure of blood to sodium nitrite resulted in the production of methemoglobin, whereas nitrate did not exhibit the same effect. The data suggest that methemoglobinemia is the primary mechanism of toxicity in nitrite poisonings. Nevertheless, further research is needed to better understand the progression of these episodes, which could help refine treatment strategies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 152-162"},"PeriodicalIF":2.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133180","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 impact of diet and regular mixers on breath alcohol concentration: A comparative study","authors":"Asena Avci Akca ,&nbsp;Atholl Johnston","doi":"10.1016/j.toxlet.2025.05.009","DOIUrl":"10.1016/j.toxlet.2025.05.009","url":null,"abstract":"<div><h3>Objective</h3><div>The use of alcoholic beverages with 'diet' mixers is becoming more popular. The purpose of this study was to assess BrAC and the pace of stomach emptying in healthy volunteers after consuming either sucrose-containing or artificially sweetened alcoholic beverages.</div></div><div><h3>Method</h3><div>This was a two-way crossover trial with an open label. The subjects consumed alcohol on two consecutive occasions conducted in the morning (9:00am-12:00 pm), once with diet coke and once with standard coke. In a randomised order, twelve healthy participants (n = 12, 8 male and 4 female) aged 19–64 years were studied twice. They drank a standardised (0.5 g/kg body weight) volume of vodka (37.5 % ABV) over a time period of 1 minute in each session, prepared with either 'regular' coke with 35 g sugar in 330 mL or 'diet' coke with artificial sweetener which is aspartame. Their BrAC was measured every 15 minutes for 3 hours. Their breath samples for stomach emptying measurement were taken separately in breath bags right after the breath alcohol measurement. The gastric half-emptying time (t_1/2) and lag phase time (tl_ag) characteristics of these breath samples were determined.</div></div><div><h3>Results</h3><div>Diet coke increased both the peak BrAC (38.3 ± 9.45 vs. 34.8 ± 6.82 μg/100 mL) and the area under the breath ethanol curve between 0 and 180 minutes (45249.0 ± 95.7 vs. 40439.25 ± 72.5 μg·min/L). Using nonlinear regression analysis, the diet drink showed a shorter half-emptying time (t_1/2) than the regular drink (100.09 ± 35.42 vs. 110.74 ± 66.71 min), while the lag phase (t_lag) was slightly longer (49.35 ± 13.52 vs. 46.63 ± 13.90 min).\"</div></div><div><h3>Conclusions</h3><div>This study emphasises the need of considering factors other than the alcohol level of a drink when determining safe quantities of intake and the potential of intoxication. The lack of sucrose in diet mixers may cause faster stomach emptying of alcohol, increasing its absorption rate into the blood, resulting in higher peak BrAC and increased exposure to other alcohol-related dangers.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 145-151"},"PeriodicalIF":2.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133211","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":"Effect of cypermethrin on thyroid follicular epithelial cell injury via the ROS-NF-κB-NLRP3 pathway","authors":"Leina Jia ,&nbsp;Xiaoning Meng ,&nbsp;Yu Ma ,&nbsp;Jinyu Luo ,&nbsp;Xiaoqi Luo ,&nbsp;Huifang Yang ,&nbsp;Jian Zhou","doi":"10.1016/j.toxlet.2025.05.008","DOIUrl":"10.1016/j.toxlet.2025.05.008","url":null,"abstract":"<div><div>Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems. Objectives: In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses. Methods: Nthy-ori 3–1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h. Results: CYP treatment enhanced oxidative damage in Nthy-ori 3–1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765 +CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level. Conclusion: The results demonstrate that CYP induces pyroptosis in Nthy-ori 3–1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 121-129"},"PeriodicalIF":2.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089403","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":"New insights into methylfuran metabolism","authors":"Daniel Bohlen ,&nbsp;Jonas Appel ,&nbsp;Lukas Eichel,&nbsp;Samuel Spengler,&nbsp;Carolin Kulosa,&nbsp;Fani Kougioumtzi,&nbsp;Simone Stegmüller,&nbsp;Nico Becker,&nbsp;Tobias Jochum,&nbsp;Elke Richling","doi":"10.1016/j.toxlet.2025.05.006","DOIUrl":"10.1016/j.toxlet.2025.05.006","url":null,"abstract":"<div><div>Methylfurans like 2,5-dimethylfuran (DMF), 2-methylfuran (2-MF), and 3-methylfuran (3‑MF) are heat-induced contaminants present in a variety of foods, such as coffee, roasted nuts and canned foods. Concerning their metabolism, toxicity, and safety information is scarce. Several studies indicate that cytochrome P450 mediated epoxidation resembles the main route of biotransformation for furan and different methylfurans, leading to the formation of highly reactive α, β-unsaturated dicarbonyls, suggested to be responsible for their reported hepatotoxic and potentially carcinogenic effects. It is assumed that side-chain oxidation by CYPs might represent an additional metabolic route for alkylfurans. The resulting alcohols may be rapidly oxidized to the corresponding carboxylic acid or serve as a substrate for sulfotransferases, which may also lead to the formation of reactive intermediates. To verify whether DMF is subject to unilateral side-chain hydroxylation, formation of 5-methyl-2-furfuryl alcohol and respective higher oxidized metabolites 5-methyl-2-furfural and 5-methyl-2-furancarboxylic acid were investigated in incubations of human liver microsomes using an established and validated GC-MS method. It was possible to monitor time- and concentration dependence of the formation of 5-methyl-2-furfuryl alcohol, while only minimal concentrations of higher oxidized metabolites were detected. In addition, side-chain oxidation of 2-MF and 3-MF were also investigated using an equivalent approach. However, formation of 2- and 3-furfuryl alcohol was not observed in human liver microsomal incubations, indicating structure dependence in metabolism of different alkyl furans.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 130-137"},"PeriodicalIF":2.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094977","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}