Archives of Toxicology最新文献

{"title":"Kinetically-derived maximal dose (KMD) confirms lack of human relevance for high-dose effects of octamethylcyclotetrasiloxane (D4)","authors":"Christopher J. Borgert, Lyle D. Burgoon, Claudio Fuentes","doi":"10.1007/s00204-024-03914-z","DOIUrl":"10.1007/s00204-024-03914-z","url":null,"abstract":"<div><p>The kinetically-derived maximal dose (KMD) is defined as the maximum external dose at which kinetics are unchanged relative to lower doses, e.g., doses at which kinetic processes are not saturated. Toxicity produced at doses above the KMD can be qualitatively different from toxicity produced at lower doses. Here, we test the hypothesis that high-dose-dependent toxicological effects of octamethylcyclotetrasiloxane (D4) occur secondary to kinetic overload. Octamethylcyclotetrasiloxane (D4) is a volatile, highly lipophilic monomer used to produce silicone polymers, which are ingredients in many consumer products and used widely in industrial applications and processes. Chronic inhalation at D4 concentrations 10<sup>4</sup> times greater than human exposures produces mild effects in rat respiratory tract, liver weight increase and pigment accumulation, nephropathy, uterine endometrial epithelial hyperplasia, non-significant increased uterine endometrial adenomas, and reduced fertility secondary to inhibition of rat-specific luteinizing hormone (LH) surge. Mechanistic studies indicate a lack of human relevance for most of these effects. Respiratory tract effects arise in rats due to direct epithelial contact with mixed vapor/aerosols and increased liver weight is a rodent-specific adaptative induction of drug-metabolizing hepatic enzymes. D4 is not mutagenic or genotoxic, does not interact with dopamine receptors, and interacts at ERα with potency insufficient to cause uterine effects or to alter the LH surge in rats. These mechanistic findings suggest high-dose-dependence of the toxicological effects secondary to kinetic overload, a hypothesis that can be tested when appropriate kinetic data are available that can be probed for the existence of a KMD. We applied Bayesian analysis with differential equations to information from kinetic studies on D4 to build statistical distributions of plausible values of the <i>K</i><sub><i>m</i></sub> and <i>V</i><sub><i>max</i></sub> for D4 elimination. From those distributions of likely <i>K</i><sub><i>m</i></sub> and <i>V</i><sub><i>max</i></sub> values, a set of Michaelis–Menten equations were generated that are likely to represent the slope function for the relationship between D4 exposure and blood concentration. The resulting Michaelis–Menten functions were then investigated using a change-point methodology known as the “kneedle” algorithm to identify the probable KMD range. We validated our <i>K</i><sub><i>m</i></sub> and <i>V</i><sub><i>max</i></sub> using out of sample data. Analysis of the Michaelis–Menten elimination curve generated from those <i>V</i><sub><i>max</i></sub> and <i>K</i><sub><i>m</i></sub> values indicates a KMD with an interquartile range of 230.0–488.0 ppm [2790–5920 mg/m<sup>3</sup>; 9.41–19.96 µM]. The KMD determined here for D4 is consistent with prior work indicating saturation of D4 metabolism at approximately 300 ppm [3640 mg/m<sup>3</sup>; 12.27 µM] and supports the hypot","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"611 - 621"},"PeriodicalIF":4.8,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969342","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}

{"title":"Serum levels of thyroxine, thyroid-stimulating hormone, and anti-thyroid peroxidase antibodies and their association with anxiety in environmentally exposed populations in Kazakhstan","authors":"Geir Bjørklund,&nbsp;Yuliya Semenova","doi":"10.1007/s00204-024-03908-x","DOIUrl":"10.1007/s00204-024-03908-x","url":null,"abstract":"<div><p>Little is known about the impact of environmental pollution on thyroid function in the non-occupationally exposed population of Kazakhstan. This study aimed to investigate serum levels of thyroxine (T4), thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase (TPO) antibodies in the environmentally exposed population of Kazakhstan in relation to symptoms of anxiety. A total of 1,388 nominally healthy individuals residing in areas exposed to three major types of environmental pollution prevalent in Kazakhstan—non-ferrous metallurgy, condensate gas extraction, and activities of the Semipalatinsk Nuclear Test Site (SNTS)—were enrolled. All comparisons were made with 493 individuals residing in settlements without industrial or military pollution. Serum-free T4, TSH, and anti-TPO levels were tested using a solid-phase chemiluminescent immunoassay. The Generalized Anxiety Disorder 7-item (GAD-7) inventory was utilized to screen for anxiety symptoms. The prevalence of subclinical hypothyroidism was significantly higher in residents of settlements near the condensate gas field than in control sites (20.3 vs. 15.0%). In comparison, the prevalence of overt hypothyroidism was insignificantly higher (0.7 vs. 0.6%). The prevalence of subclinical hyperthyroidism was insignificantly higher in residents of settlements around the SNTS. The prevalence of overt hyperthyroidism was insignificantly higher in residents of areas proximal to the condensate gas field compared to the controls. The prevalence of both normal and elevated serum levels of anti-TPO antibodies did not differ significantly between different sites. Moderate and severe anxiety symptoms were the least common in residents of the two control sites (5.9%). This study carries potential implications for tailored public health interventions and policies.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"825 - 833"},"PeriodicalIF":4.8,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03908-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969364","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}

{"title":"Accumulation of chlorinated paraffins in adipocytes is determined by cellular lipid content and chlorination level.","authors":"Nikola Vrzáčková, Jakub Tomáško, Petr Svoboda, Vojtěch Škop, Magdalena Melčová, Jana Dudová, Jaroslav Zelenka, Jana Pulkrabová, Tomáš Ruml","doi":"10.1007/s00204-024-03956-3","DOIUrl":"https://doi.org/10.1007/s00204-024-03956-3","url":null,"abstract":"<p><p>Chlorinated paraffins (CPs) are environmental pollutants extensively used in industries. While the use of short-chain chlorinated paraffins (SCCPs) has been restricted since 2017, the use of medium-chain chlorinated paraffins (MCCPs) has risen as their replacement. Due to lipophilic character, it can be expected that CPs enter the cells; however, the in vitro accumulation potential of CPs remains poorly understood. In this study, we aimed to explore the ability of SCCPs and MCCPs to accumulate in fat cells. We utilized an in vitro model of mouse 3T3-L1 preadipocytes and adipocytes. Using gas chromatography coupled with high-resolution mass spectrometry operated in negative chemical ionization mode, we determined the intracellular amounts of CPs. These compounds accumulated at rates of 8.5 ± 0.1 µg/g_cells/h for SCCPs and 7.8 ± 0.3 µg/g_cells/h for MCCPs when an initial concentration of 120 ng/ml was present in the medium. This rate increased approximately tenfold when the concentration of CPs was raised to 1200 ng/ml. CPs content in adipocytes steadily increased over 5 days, whereas preadipocytes accumulated 15-20 times less CPs. This highlights the importance of cellular lipid content, which was about 12 times higher in adipocytes. Furthermore, we found that the level of chlorine content in the CPs molecules significantly influenced their accumulation. Our results demonstrate that MCCPs exhibit a similar accumulation potential to SCCPs, with lipid content playing a crucial role. As with SCCPs, restrictions on the use of MCCPs in industry should be considered to mitigate their environmental and health impacts.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943372","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}

{"title":"E-cigarettes increase the risk of adenoma formation in murine colorectal cancer model.","authors":"Ibrahim M Sayed, Anirban Chakraborty, Kaili Inouye, Leanne Dugan, Stefania Tocci, Ira Advani, Kenneth Park, Samvel Gaboyan, Nikita Kasaraneni, Benjamin Ma, Tapas K Hazra, Soumita Das, Laura E Crotty Alexander","doi":"10.1007/s00204-024-03932-x","DOIUrl":"10.1007/s00204-024-03932-x","url":null,"abstract":"<p><p>E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development. A mouse model of human familial adenomatous polyposis (CPC-APC) was utilized wherein a mutation in the adenomatous polyposis coli (APC) gene, CDX2-Cre-APC^Min/+, leads to the development of colon adenomas within 11-16 weeks. Mice were exposed to air (controls), E.cig vaping, cig, or both (dual exposure). After 4 weeks of 2 h exposures per day (1 h of each for dual exposures), the colon was collected and assessed for polyp number and pathology scores by microscopy. Expression of inflammatory cytokines and cancer stem cell markers were quantified. DNA damage such as double-strand DNA breaks was evaluated by immunofluorescence, western blot, and gene-specific long amplicon qPCR. DNA repair enzyme levels (NEIL-2, NEIL-1, NTH1, and OGG1) were quantified by western blot. Proliferation markers were assessed by RT-qPCR and ELISA. CPC-APC mice exposed to E.cig, cig, and dual exposure developed a higher number of polyps compared to controls. Inflammatory proteins, DNA damage, and cancer stemness markers were higher in E-cig, cig, and dual-exposed mice as well. DNA damage was found to be associated with the suppression of DNA glycosylases, particularly with NEIL-2 and NTH1. E.cig and dual exposure both stimulated cancer cell stem markers (CD44, Lgr-5, DCLK1, and Ki67). The effect of E.cigs on polyp formation and CRC development was less than that of cigs, while dual exposure was more tumorigenic than either of the inhalants alone. E.cig vaping promotes CRC by stimulating inflammatory pathways, mediating DNA damage, and upregulating transcription of cancer stem cell markers. Critically, combining E.cig vaping with cig smoking leads to higher levels of tumorigenesis. Thus, while the chemical composition of these two inhalants, E.cigs and cigs, is highly disparate, they both drive the development of cancer and when combined, a highly common pattern of use, they can have additive or synergistic effects.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943376","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}

{"title":"Dynamics in zebrafish development define transcriptomic specificity after angiogenesis inhibitor exposure.","authors":"Julia Nöth, Paul Michaelis, Lennart Schüler, Stefan Scholz, Janet Krüger, Volker Haake, Wibke Busch","doi":"10.1007/s00204-024-03944-7","DOIUrl":"https://doi.org/10.1007/s00204-024-03944-7","url":null,"abstract":"<p><p>Testing for developmental toxicity is an integral part of chemical regulations. The applied tests are laborious and costly and require a large number of vertebrate test animals. To reduce animal numbers and associated costs, the zebrafish embryo was proposed as an alternative model. In this study, we investigated the potential of transcriptome analysis in the zebrafish embryo model to support the identification of potential biomarkers for key events in developmental toxicity, using the inhibition of angiogenesis as a proof of principle. Therefore, the effects on the zebrafish transcriptome after exposure to the tyrosine kinase inhibitors, sorafenib (1.3 µM and 2.4 µM) and SU4312 (1 µM, 2 µM, and 5 µM), and the putative vascular disruptor compound rotenone (25 nM and 50 nM) were analyzed. An early (2 hpf-hours post fertilization) and a late (24 hpf) exposure start with a time resolved transcriptome analysis was performed to compare the specificity and sensitivity of the responses with respect to anti-angiogenesis. We also showed that toxicodynamic responses were related to the course of the internal concentrations. To identify differentially expressed genes (DEGs) the time series data were compared by applying generalized additive models (GAMs). We observed mainly unspecific developmental toxicity in the early exposure scenario, while a specific repression of vascular related genes was only partially observed. In contrast, differential expression of vascular-related genes could be identified clearly in the late exposure scenario. Rotenone did not show angiogenesis-specific response on a transcriptomic level, indicating that the observed mild phenotype of angiogenesis inhibition may represent a secondary effect.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943375","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}

{"title":"Non-invasive in vitro NAM for the detection of reversible and irreversible eye damage after chemical exposure for GHS classification purposes (ImAi).","authors":"Nicola Knetzger, Norman Ertych, Tanja Burgdorf, Joelle Beranek, Michael Oelgeschläger, Jana Wächter, Annika Horchler, Stefanie Gier, Maike Windbergs, Susann Fayyaz, Fabian A Grimm, Georg Wiora, Christian Lotz","doi":"10.1007/s00204-024-03940-x","DOIUrl":"https://doi.org/10.1007/s00204-024-03940-x","url":null,"abstract":"<p><p>The potential risk of chemicals to the human eye is assessed by adopted test guidelines (TGs) for regulatory purposes to ensure consumer safety. Over the past decade, the Organization for Economic Co-operation and Development (OECD) has approved new approach methodologies (NAMs) to predict chemical eye damage. However, existing NAMs remain associated with limitations: First, no full replacement of the in vivo Draize eye test due to limited predictability of severe/mild damage was reached. Second, the existing NAMs do not allow reliable differentiation between reversible and irreversible eye damage. Especially the prediction of tissue recovery remains challenging in vitro. Existing in vitro NAMs are based on destructive analysis with no consideration of tissue recovery. In this study, we developed a standalone eye-irritation test method based on non-invasive impedance spectroscopy (ImAi) to discriminate between damaging and irritating chemicals. Tissue effects were analyzed via transepithelial electrical resistance (TEER) measurements of human in vitro epithelial models over 14 days. The TEER was performed using a developed impedance spectrometer. For development of the EIT, a chemical reference list of 329 chemicals was compiled. The applicability of the ImAi-test was exemplified by the discrimination of Cat. 1 vs. Cat. 2 for 23 reference chemicals. Correct classification was achieved for 90.9% of Cat. 1 and 83.3% of Cat. 2 chemicals. Our non-invasive in vitro test overcomes the limitations of Cat. 2 classification of the existing in vitro methods and provides for the first time a non-animal test method that can fully replace the Draize eye test.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943377","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}

{"title":"Disentangling the role of selenium in antagonizing the toxicity of arsenic and cadmium","authors":"Iwona Zwolak","doi":"10.1007/s00204-024-03918-9","DOIUrl":"10.1007/s00204-024-03918-9","url":null,"abstract":"<div><p>Cadmium (Cd) and inorganic arsenic (As) compounds are considered to be among the major public health hazards. This is due to both the high intrinsic toxicity of these substances and the often difficult to avoid exposure of the general population through contaminated water and food. One proposed method to reduce the toxic effects of As and Cd on animals and humans is the use of selenium (Se). As discussed in our previous article, laboratory studies show that this micronutrient can have a beneficial effect on the detoxification of As and Cd in the body through the formation of non-toxic complexes with these elements, as well as through the antioxidant effects of selenoproteins. New data that have emerged in recent years allow for a clearer description of the interaction between Se and As and Se and Cd. Human studies show that optimal levels of Se can have a beneficial effect in reducing the toxic effects associated with exposure to As or Cd. However, as Se levels in the body increase, the protective effects of Se may be reversed. Recent laboratory studies confirm the antagonistic effects of medium doses of Se toward Cd and As through the formation of nontoxic complexes, antioxidant, anti-inflammatory effects, and induction of pro-survival pathways in cells. In conclusion, Se has a complex effect on As and Cd toxicity, with both benefits and potential risks, depending on the form of Se and its dose as a supplement or the status (level) of this micronutrient in the body.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"513 - 540"},"PeriodicalIF":4.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943373","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}

{"title":"Metabolomics and proteomics: synergistic tools for understanding snake venom inhibition.","authors":"Sana S Hussain, J Danie Kingsley","doi":"10.1007/s00204-024-03947-4","DOIUrl":"https://doi.org/10.1007/s00204-024-03947-4","url":null,"abstract":"<p><p>Snake envenomation presents a significant global health challenge, especially in rural areas of tropical and subtropical regions. Traditional antivenom therapies face limitations related to efficacy, availability, and specificity, prompting a need for novel approaches. Recent advancements in omics technologies, particularly metabolomics and proteomics, have enhanced our understanding of snake venom composition, toxicity, and potential therapeutic strategies. Metabolomics allows for the study of metabolic changes induced by venom, providing insights into disrupted pathways and possible inhibitors. Proteomics facilitates the identification and characterization of venom proteins, unveiling their interactions with therapeutic agents. Integrative databases such as the Snake Venom Database (SVDB) and STAB Profiles enhance this research by cataloging venom components and aiding in the analysis of venom-antivenom interactions. The combined application of metabolomics and proteomics has led to the identification of crucial metabolic pathways and protein targets essential for effective venom inhibition. This review explores current advances in these fields, emphasizing the role of omics in identifying novel inhibitors and developing next-generation antivenoms. The integrated approach of metabolomics and proteomics offers a comprehensive understanding of snake venom biology, paving the way for more effective and tailored therapeutic solutions for envenomation.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930481","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}

{"title":"Grouping of chemicals for safety assessment: the importance of toxicokinetic properties of salicylate esters.","authors":"Abdulkarim Najjar, Sébastien Grégoire, Beate Nicol, Andreas Natsch, Nazanin Golbamaki, Fanny Boisleve, Amaia Irizar, Brian Wall, Angus Swinscoe, Valérie Masini-Etévé, Kaushal Joshi, Anne Marie Api, Peter Griem, Allison Reis, Nicola J Hewitt, Estefania Cardamone","doi":"10.1007/s00204-024-03935-8","DOIUrl":"https://doi.org/10.1007/s00204-024-03935-8","url":null,"abstract":"<p><p>Grouping of chemicals has been proposed as a strategy to speed up the screening and identification of potential substances of concern among the broad chemical universe under REACH. Such grouping is usually based on shared structural features and should only be used for the prioritization objectives. However, additional considerations (as well as structural similarity) are needed, e.g., mode of action, metabolic pathways, chemical reaction products and physicochemical properties, when regulatory management measures are considered (such as restriction, harmonized classification and labeling). Guidance documents from the European Chemicals Agency (ECHA) recommend considering toxicokinetic information to enhance the robustness of the grouping; however, examples of this approach are lacking. Therefore, this paper shares findings on chemical grouping based on ADME data generated for multiple esters of salicylic acid. These differ with respect to chain length and branching of the alcohol moiety of salicylic acid ester, resulting in a wide range of lipophilicity (LogP 0.21-10.88). Since LogP impacts skin absorption, as well as hydrolysis by carboxylesterases, the bioavailability and thus internal exposure to topically applied salicylate esters can vary considerably. Therefore, we collected skin absorption and metabolism data for 41 salicylates using in vitro testing and in silico models and combined the information to group them according to their potential systemic exposure to the major metabolite, salicylic acid. The results show that, despite a similar general chemical structure, their toxicokinetics vary considerably, indicating the need for better understanding of ADME properties to assess the internal exposure for sound risk assessment.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926302","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}

{"title":"In vitro metabolism of seven arolyl-derived fentanyl-type new psychoactive substances.","authors":"Xuan Luo, Qiaotong Chen, Kejian Huang, Xiaofeng Liu, Ning Yang, Qiulian Luo","doi":"10.1007/s00204-024-03937-6","DOIUrl":"https://doi.org/10.1007/s00204-024-03937-6","url":null,"abstract":"<p><p>Over the past decade, fentanyl-type new psychoactive substances (F-NPS) have emerged as the most representative synthetic opioids in third-generation drugs. These substances are characterized by their \"low\" fatal dose and parent drug levels in biological matrices, \"fast\" rates of derivatization and metabolism, and \"many\" derivatization sites and analogs. The low levels of parent fentanyl NPS in biological matrices complicate their detection, necessitating the use of characteristic metabolites as biomarkers for forensic analysis. Moreover, the ongoing emergence of arolyl-derived F-NPS further challenges forensic laboratories in accurately identifying the parent drug from its metabolites. To address this issue, in this study, the in vitro phase I metabolism of seven arolyl-derived F-NPS was studied using a human liver microsome model. Metabolites were analyzed by liquid chromatography-ion trap tandem time-of-flight mass spectrometry. Using density functional theory, the structural characteristics and their effects on amide hydrolysis, N-dealkylation, and oxidation metabolism were clarified. Amide hydrolysis was influenced by the positive charge of the carbonyl carbon and the 2-substituent effect on the aryl groups. N-dealkylation, β-monohydroxylation, N-oxidation, and phenyl group monohydroxylation in the tail were less affected by structural changes in the head. The former two were the major metabolites and exhibited competition. The relative contents of N-oxidation and phenyl group monohydroxylation in the tail were relatively stable at 4% and 13%, respectively. Furthermore, the β-C adjacent to the nitrogen on the piperidine ring was susceptible to oxidation, leading to the formation of the monohydroxylation metabolite. The results of this study may enhance our understanding of the in vitro metabolism of arolyl-derived F-NPS, and potentially all F-NPS, providing important data and theoretical support for predicting their in vivo metabolism in the future.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920368","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}