Archives of Toxicology最新文献_第6页

SIRT3 regulates PFKFB3-mediated glycolysis to attenuate cisplatin-induced ototoxicity both in vivo and in vitro.

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-13 DOI: 10.1007/s00204-025-03975-8

Wei Tang, Shimin Zong, Peiyu Du, Xuan Yu, Ting Li, Bo Liu, Yu Zhong, Wenyang Lei, Wenting Yu, Hongjun Xiao

{"title":"SIRT3 regulates PFKFB3-mediated glycolysis to attenuate cisplatin-induced ototoxicity both in vivo and in vitro.","authors":"Wei Tang, Shimin Zong, Peiyu Du, Xuan Yu, Ting Li, Bo Liu, Yu Zhong, Wenyang Lei, Wenting Yu, Hongjun Xiao","doi":"10.1007/s00204-025-03975-8","DOIUrl":"https://doi.org/10.1007/s00204-025-03975-8","url":null,"abstract":"<p><p>Cochlear hair cell death is the primary cause of cisplatin-induced ototoxicity, currently lacking widely applicable clinical methods for effective prevention and treatment. In this study, an in vivo cisplatin-induced ototoxicity model was established by intraperitoneal injection of 12 mg/kg cisplatin. We found that ablation of SIRT3 exacerbates cisplatin-induced hearing loss and cochlear hair cell damage. An in vitro cisplatin-induced ototoxicity model was established using 5 µM cisplatin in cochlear explants and OC-1 cells. We found that the absence of SIRT3 impairs cochlear hair cell glycolytic metabolism, leading to excessive accumulation of ROS and significant reduction in MMP levels, thereby promoting apoptosis. In contrast, overexpression of SIRT3 in OC-1 cells promotes cochlear hair cell survival and reduces cochlear hair cell apoptosis. Inhibition of PFKFB3 reduces glycolytic metabolism in OC-1 cells, and the protective effect conferred by SIRT3 overexpression is lost. In summary, the protective effect of SIRT3 may be mediated by the regulation of PFKFB3-dependent glycolysis and the mitigation of cisplatin-induced excessive ROS accumulation.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-13 DOI: 10.1007/s00204-025-03971-y

Julie Sanders, Roel Anthonissen, George E. Johnson, Tamara Vanhaecke, Birgit Mertens

{"title":"A benchmark concentration-based strategy for evaluating the combined effects of genotoxic compounds in TK6 cells","authors":"Julie Sanders, Roel Anthonissen, George E. Johnson, Tamara Vanhaecke, Birgit Mertens","doi":"10.1007/s00204-025-03971-y","DOIUrl":"10.1007/s00204-025-03971-y","url":null,"abstract":"<div><p>Chemical risk assessment has historically focused on single compounds, neglecting the implications of combined exposures. To bridge this gap, several methodologies, such as concentration addition (CA) and independent action (IA), have been developed. However, a systematic, consistent, and integrated approach across various legislative frameworks is still lacking. The assessment of combined effects of genotoxicants is even more challenging, as genotoxicity data are typically evaluated qualitatively, without considering the effect size. This study aimed to develop a quantitative approach for evaluating the combined effects of genotoxic compounds with both similar and dissimilar modes of action (MoA), based on the benchmark concentration (BMC) principle. A proof-of-concept study was conducted using the in vitro micronucleus (MNvit) test to examine two types of binary mixtures: ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS), which share similar MoA, and MMS and etoposide (ETP), which have dissimilar MoA. The methodology involved collecting data for individual compounds, calculating BMC values, composing mixtures with different ratios and inducing various effect levels, testing these mixtures, and comparing the experimental results with the modelled data to verify additivity. The findings indicated that for both mixtures, the experimental responses aligned with the predicted additive effects, supporting the validity of the additivity principle. This study highlights the potential of an optimized BMC-based approach as a robust framework for testing chemical mixtures. It should be adopted in future studies to evaluate a wider range of genotoxic compounds, offering a more comprehensive and quantitative strategy for assessing combined chemical exposures.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1581 - 1589"},"PeriodicalIF":4.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-025-03971-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Micrurus lemniscatus venom stimulates leukocyte functions in vivo

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-13 DOI: 10.1007/s00204-025-03970-z

Luciana Lyra Casais-e-Silva, Larissa Faustina Cruz, Valdison P. dos Reis, Mauro V. Paloschi, Catarina Teixeira, Juliana P. Zuliani, Sulamita da Silva Setubal

{"title":"Micrurus lemniscatus venom stimulates leukocyte functions in vivo","authors":"Luciana Lyra Casais-e-Silva, Larissa Faustina Cruz, Valdison P. dos Reis, Mauro V. Paloschi, Catarina Teixeira, Juliana P. Zuliani, Sulamita da Silva Setubal","doi":"10.1007/s00204-025-03970-z","DOIUrl":"10.1007/s00204-025-03970-z","url":null,"abstract":"<div><p>While <i>Micrurus</i> venoms are primarily recognized for inducing neurotoxic effects, experimental findings have also documented additional manifestations such as local effects such as edema, myotoxicity, and inflammation. However, limited information is available regarding the impact of <i>Micrurus</i> venom on leukocyte functions. In this study, we investigated the in vivo effects of <i>Micrurus lemniscatus</i> venom (ML venom) on peritoneal leukocyte functions. Intraperitoneal (i.p.) injection of ML venom stimulated leukocyte migration, particularly at lower doses, with predominance of mononuclear cells. Both doses also triggered the release of cytokines (TNF-α, IL-1β, and IL-6) three hours after injection. Additionally, ML venom elicited the production of reactive oxygen species (ROS) and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), as well as enhanced phagocytosis, along with the release of dsDNA and lipid droplets by these cells. This study represents the first demonstration of peritoneal leukocyte activation by <i>Micrurus lemniscatus</i> venom.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1591 - 1603"},"PeriodicalIF":4.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comparative toxicological evaluation of emerging nicotine analogs 6-methyl nicotine and nicotinamide: a scoping review

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-12 DOI: 10.1007/s00204-025-03960-1

Felix Effah, Yehao Sun, Karen Lin, Irfan Rahman

{"title":"A comparative toxicological evaluation of emerging nicotine analogs 6-methyl nicotine and nicotinamide: a scoping review","authors":"Felix Effah, Yehao Sun, Karen Lin, Irfan Rahman","doi":"10.1007/s00204-025-03960-1","DOIUrl":"10.1007/s00204-025-03960-1","url":null,"abstract":"<div><p>Thermal degradation of flavored e-liquids in e-cigarettes (e-cigs) produces oxidants, volatile organic compounds, and heavy metals. Inhalation toxicology studies have revealed exposure to these toxicants may be toxic to humans. These studies informed the FDA’s regulation of nicotine-containing E-cigs under the Tobacco Regulation Act (TRA) (2020) and the banning of all flavors in E-cig bars apart from tobacco and menthol. Furthermore, tobacco companies aiming to sell nicotine products on the US market ought to submit a premarket tobacco product application (PMTA) and obtain approval from the FDA before marketing. Nonetheless, because the PMTA process is lengthy/complicated, vape/tobacco companies utilized a loophole in the TRA (2020) and have introduced nicotine analogs in E-cig bars, such as 6-methyl nicotine (6-MN) and nicotinamide, which are not derived from nicotine or tobacco. These companies claim these analogs to be ‘safer’ alternatives to nicotine while providing similar satisfaction as nicotine. However, the safety profiles of these analogs are entirely unknown. Therefore, in this review, we have extrapolated the current literature on 6-MN and nicotinamide, and speculated their potential mode of toxicity through alterations in intracellular ROS and activation of nicotinic acetylcholine receptors, transient receptor potential ankyrin-1, and NF-κB. These biomolecules are pivotal in the onset and regulation of pulmonary diseases such as COPD, asthma, and lung tumorigenesis/remodeling. Thus, primary research is urgently warranted to inform regulatory agencies of these emerging nicotine analogs' potential adverse health effects. This article provides insightful information on emerging vape products' potential toxicity for environmental toxicology research and regulation.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1333 - 1340"},"PeriodicalIF":4.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of the toxicity of combustion smokes at the air–liquid interface: a comparison between two lung cell models and two exposure methods

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-11 DOI: 10.1007/s00204-025-03964-x

A. Ashrin, E. Anna, E. Peyret, G. Barbier, Maxime Floreani, C. Pointart, D. Medus, G. Fayet, P. Rotureau, T. Loret, G. Lacroix

{"title":"Evaluation of the toxicity of combustion smokes at the air–liquid interface: a comparison between two lung cell models and two exposure methods","authors":"A. Ashrin, E. Anna, E. Peyret, G. Barbier, Maxime Floreani, C. Pointart, D. Medus, G. Fayet, P. Rotureau, T. Loret, G. Lacroix","doi":"10.1007/s00204-025-03964-x","DOIUrl":"10.1007/s00204-025-03964-x","url":null,"abstract":"<div><p>In vitro tests at the air–liquid interface (ALI) represent valuable alternatives to animal experiments to assess the acute toxicity of inhalable compounds. However, these methods still need to be characterized for the toxicity evaluation of complex mixtures such as combustion smokes. In this study, Alveolar type I or Alveolar type 2 cells in co-culture with macrophages were investigated as models for evaluating the acute toxicity of complex mixtures at the air–liquid interface. In that purpose, smokes/obscurants were generated from pyrotechnic devices of known toxic potentials in a 1.3 m<sup>3</sup> chamber and the co-cultures were exposed to smokes in static (directly in the chamber) or in dynamic using Vitrocell® modules. After exposure to smokes, static exposure induced higher cell mortality compared to dynamic, likely due to an increased dose. Nevertheless, we could still discriminate between a high-toxic (TA) and a low-toxic (RP) smoke using both exposure methods. Due to important cell mortality in static, oxidative and inflammatory potentials were only evaluated in dynamic mode. Reactive oxygen species were generated in response to smokes in hAELVI-THP-1 but not in A549-THP-1. After exposure to TA, increased levels of IL-1β, IL-6, and TNF-α were released by A549-THP-1 compared to the control while hAELVI-THP-1 released significant amount of IL-8. No inflammation was reported following exposure to RP, likely due to important cell mortality. Although discrepancies exist between the two cell models and exposure modes, these results suggest that both co-cultures and exposure methods remain promising for evaluating the toxicity of inhalable mixtures such as smokes.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1471 - 1484"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polybrominated biphenyls induce liver injury by disrupting the KEAP1/Nrf2/SLC7A11 axis leading to impaired GSH synthesis and ferroptosis in hepatocytes 多溴联苯通过破坏 KEAP1/Nrf2/SLC7A11 轴，导致肝细胞中 GSH 合成受损和铁变态反应，从而诱发肝损伤。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-11 DOI: 10.1007/s00204-025-03973-w

Longteng Jin, Ya Zhang, Yuhan Xia, Qifang Wu, Huanjuan Yan, Haibin Tong, Maoping Chu, Zhengwang Wen

{"title":"Polybrominated biphenyls induce liver injury by disrupting the KEAP1/Nrf2/SLC7A11 axis leading to impaired GSH synthesis and ferroptosis in hepatocytes","authors":"Longteng Jin, Ya Zhang, Yuhan Xia, Qifang Wu, Huanjuan Yan, Haibin Tong, Maoping Chu, Zhengwang Wen","doi":"10.1007/s00204-025-03973-w","DOIUrl":"10.1007/s00204-025-03973-w","url":null,"abstract":"<p>Polybrominated biphenyls (PBBs) are persistent organic pollutants (POPs) widespread in the environment, presenting significant health hazards due to their bioaccumulation, particularly in liver. Ferroptosis, an iron-dependent form of cell death, has not been previously linked to PBBs-induced hepatotoxicity. This study investigated whether PBBs induce hepatotoxicity through ferroptosis and the toxicological mechanism using mice and THLE-2 cells models exposed to PBB mixture (BP-6). Histopathological and biochemical analyses revealed that BP-6 exposure-induced hepatic injury, oxidative stress, and inflammatory response in mice. BP-6 exposure induced a significant increase in Fe<sup>2+</sup> content and a decrease in FTH1, SLC7A11 and GPX4 protein expression in hepatocytes, resulting in severe lipid peroxide accumulation and GSH depletion. Ferroptosis inhibitors, Fer-1 and DFO, reversed the iron metabolism disruption caused by BP-6, underscoring the critical role of ferroptosis in BP-6-induced liver injury. Mechanistically, BP-6 exposure impaired GSH synthesis by preventing Nrf2 nuclear translocation and <i>Slc7a11</i> transcription through upregulating KEAP1 levels. <i>Keap1</i> knockdown or <i>Slc7a11</i> overexpression reversed BP-6-induced lipid peroxide accumulation and GSH depletion, confirming the involvement of ferroptosis in BP-6-induced hepatotoxicity. In addition, curcumin, a natural Nrf2 agonist, significantly alleviated BP-6-induced ferroptosis and liver injury in vitro and in vivo by restoring SLC7A11 protein expression and GSH synthesis. These findings elucidate the toxicological mechanism of PBBs and suggest potential therapeutic strategies to counteract PBBs exposure.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1545 - 1559"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nuclear receptor coactive 4-mediated ferritinophagy: a key role of heavy metals toxicity

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-10 DOI: 10.1007/s00204-025-03963-y

Wan-Xue Xu, Xue Wen, Yi-Tong Fu, Jie Yang, Han Cui, Rui-Feng Fan

引用次数: 0

Metabolic disruption by mycotoxins: focus on metabolic endpoints steatosis, adipogenesis and glucose metabolism in vivo and in vitro.

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-09 DOI: 10.1007/s00204-025-03957-w

Tia Heikkinen, Jenni Küblbeck, Jaana Rysä

{"title":"Metabolic disruption by mycotoxins: focus on metabolic endpoints steatosis, adipogenesis and glucose metabolism in vivo and in vitro.","authors":"Tia Heikkinen, Jenni Küblbeck, Jaana Rysä","doi":"10.1007/s00204-025-03957-w","DOIUrl":"https://doi.org/10.1007/s00204-025-03957-w","url":null,"abstract":"<p><p>Metabolic disruption encompasses the processes leading to adverse effects to major metabolic organs, such as liver and pancreas after exposure to e.g., environmental chemicals. As some mycotoxins act as endocrine disruptors, their structural similarity may lead to effects in lipid and glucose metabolism as well. Via systematic literature search, we mapped the potential of mycotoxins to cause metabolic disruption. Our systematic data search involved mycotoxin keywords combined with metabolic disruption keywords. The retrieved 31 studies revealed 24 in vivo studies, and 18 in vitro studies in total of 13 different mycotoxins. Most studied parameters were triglycerides from blood or liver, followed by total cholesterol and glucose or insulin levels. In vitro studies most often aimed to reveal mechanisms of metabolic disruption, but common metabolic parameters (lipid or cholesterol accumulation). In general, mycotoxin exposure showed a trend towards positive metabolic effects, such as reduction of blood triglycerides levels. Emodin was the most studied mycotoxin. Other mycotoxins were studied in one to three studies. Positive effects were also identified for equisetin, fumonisin B1, fumigaclavine C and ergostatrien-3-B-ol. Adverse effects (e.g. increased lipid deposition to liver) were identified for aflatoxin B1, ochratoxin A, deoxynivalenol, citreoviridin, T-2 toxin and paxilline. As demonstrated by the evaluated in vivo and in vitro studies, mycotoxins seem to have more positive than negative effects on metabolism. However, based on the available data, a general conclusion on the role of mycotoxins as a group cannot be made.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dexamethasone mitigates sulfur mustard-induced stem cell deficiency in vivo in rabbit limbal tissue by reducing inflammation and oxidative stress

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-04 DOI: 10.1007/s00204-025-03961-0

Rama Kant, Neha Mishra, Kushal Kandhari, Laura Saba, Neera Tewari-Singh, J. Mark Petrash, Chapla Agarwal, Rajesh Agarwal

{"title":"Dexamethasone mitigates sulfur mustard-induced stem cell deficiency in vivo in rabbit limbal tissue by reducing inflammation and oxidative stress","authors":"Rama Kant, Neha Mishra, Kushal Kandhari, Laura Saba, Neera Tewari-Singh, J. Mark Petrash, Chapla Agarwal, Rajesh Agarwal","doi":"10.1007/s00204-025-03961-0","DOIUrl":"10.1007/s00204-025-03961-0","url":null,"abstract":"<div><p>Sulfur mustard (SM) exposure induces ocular injury primarily to the cornea, limbus, and sclera. Although corneal injuries have been studied in detail, there is a dearth of literature on the effects of SM on limbus, particularly mechanisms underlying its compromised functioning, causing limbal stem cell deficiency (LSCD). LSCD causes impaired corneal repair leading to persistent epithelial defects, mustard gas keratopathy, and prolonged inflammation, resulting in total blindness in case of severe damage. Notably, dexamethasone (Dex) has been reported to treat SM-induced corneal injuries effectively; however, its efficacy for SM-induced limbus injury has not been studied. Hence, delayed/persistent structural damage (H&E and trichrome staining) and loss of LSCs [ΔNp63; immunofluorescence (IF)] in the limbus at day 28 post-SM exposure were assessed. Thereafter, in-depth proteomic analysis (LC–MS/MS) of SM exposed, Dex treated, and control limbal tissues (New Zealand white male rabbits) was performed. SM exposure significantly modulated the expression profile of 66 proteins, of which 62 were significantly reversed with Dex; thus, markedly inhibiting/hindering SM-induced limbal injury. Ingenuity Pathway Analysis predicted the primary involvement of (1) inflammation and immune response-associated pathways via dysregulation of defensin-5, eosinophil peroxidase, corticostatin-6, myeloperoxidase, and cathepsin C; and (2) drug/toxin metabolism and oxidative stress via GSTs, and ALDH1As modulations. IF analysis confirmed that Dex treatment significantly reversed SM-induced increases in human neutrophil peptides, defensin-5, and cathepsin C expression by 68%, 77%, and 90%, respectively. Thus, Dex markedly mitigated SM-induced limbal tissue injuries and prevented LSCD, via SM-induced inflammatory and oxidative stress inhibition, in our studies.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1531 - 1543"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicokinetics and analytical toxicology of the phenmetrazine-derived new psychoactive substance 3,4-methylenedioxyphenmetrazine studied by means of in vitro systems 通过体外系统研究苯并吡嗪衍生的新精神活性物质 3,4-亚甲二氧基苯并吡嗪的毒代动力学和分析毒理学。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2025-02-04 DOI: 10.1007/s00204-025-03965-w

Matthias D. Kroesen, Tanja M. Gampfer, Lea Wagmann, Markus R. Meyer

{"title":"Toxicokinetics and analytical toxicology of the phenmetrazine-derived new psychoactive substance 3,4-methylenedioxyphenmetrazine studied by means of in vitro systems","authors":"Matthias D. Kroesen, Tanja M. Gampfer, Lea Wagmann, Markus R. Meyer","doi":"10.1007/s00204-025-03965-w","DOIUrl":"10.1007/s00204-025-03965-w","url":null,"abstract":"<div><p>Compounds derived from known drugs are usually brought on the new psychoactive substance (NPS) market without any previous toxicological risk assessment. The European Union Drugs Agency issued an EU early notification for 3,4-methylenedioxyphenmetrazine (MDPM) in 2024. It is structurally related to the stimulants amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), and phenmetrazine and expected to have similar effects. So far, no scientific reports are available describing its toxicokinetic and analytical profile. This study aimed to provide such data to allow a thorough risk assessment and to ease its analytical detectability in forensic and clinical toxicology and doping control. Data reported include the in vitro plasma protein binding, the in vitro half-life and in vitro metabolism of MDPM by human liver microsomes and S9 fraction (pHLS9) and by HepaRG cells. A monooxygenase mapping and the in vitro cytochrome P450 inhibition of MDPM was elucidated. Results showed that HepaRG cells and pHLS9 formed the same MDPM metabolites via demethylenation and <i>O</i>-methylation and that MDPM has a low plasma protein binding and is a low-turnover drug. Monooxygenase mapping revealed that the demethylenation was exclusively CYP2D6-mediated. MDPM showed strong inhibition of CYP2D6 and moderate inhibition of CYP1A2 and CYP3A4. Polymorphisms or the simultaneous intake of substances that are also CYP2D6 substrates can have a considerable impact on the toxicity of MDPM. Based on in vitro data, the demethylenyl-methyl metabolite of MDPM and the parent compound are recommended as analytical urine screening targets.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1407 - 1416"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-025-03965-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0