Toxicology最新文献

{"title":"Advances in antituberculosis drug-induced liver injury: Molecular mechanisms, genetic insights, and emerging animal-free prediction models","authors":"Rui Yang ,&nbsp;Zhu Jin ,&nbsp;Xueli Jin ,&nbsp;Yiming Li ,&nbsp;Decheng Wang ,&nbsp;Jin Chao","doi":"10.1016/j.tox.2025.154359","DOIUrl":"10.1016/j.tox.2025.154359","url":null,"abstract":"<div><div>Approximately 10 million tuberculosis patients worldwide require drug therapies annually. However, prolonged use of tuberculocidal drugs in combination regimens may induce hepatotoxicity, ranging from asymptomatic serum transaminase elevation to acute liver failure, which often necessitates treatment discontinuation. Antituberculosis drug-induced liver injury (AT-DILI) represents a predominant cause of clinical DILI in humans globally. The multifactorial and incompletely uncovered mechanisms underlying AT-DILI necessitate human-relevant models to predict liver injury progression and guide timely interventions. This review synthesizes current knowledge of mechanisms implicated in AT-DILI, focusing on metabolic activation of first-line drugs, immune-mediated hepatocyte damage, and cholestasis via transporter inhibition. Genetic polymorphisms in <em>N-acetyltransferase 2</em>, <em>Cytochrome P450 2E1</em> and glutathione S-transferase genes are highlighted as critical determinants of interindividual susceptibility. Meanwhile, we critically evaluate the evolution of animal-free prediction models, spanning <em>in vitro</em> systems (2D hepatocytes and 3D culture system including hepatic spheroid, organoids, microfluidic systerms, and 3D bioprinting) to computational approaches such as quantitative structure-activity relationship modeling and machine learning. These models address ethical concerns, interspecies variabilities, and translatability limitations inherent to traditional animal studies while enabling high-throughput toxicity profiling. Despite advancements, challenges persist in standardizing experimental architectures, reducing operational costs, establishing physiological fidelity, and validating computational predictions. Robust characterization of emerging animal-free platforms including spanning the physiological fidelity, multi-omics integration capacity, and clinical translatability is therefore indispensable for advancing regulatory-ready frameworks toward safer tuberculosis therapy.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154359"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145639103","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":"Mixture toxicity revisited: A translational review of experimental evidence from animal models to human health risk assessment","authors":"Jose L. Domingo","doi":"10.1016/j.tox.2025.154372","DOIUrl":"10.1016/j.tox.2025.154372","url":null,"abstract":"<div><div>This review examines research investigating how simultaneous exposure to multiple chemicals affects biological systems, highlighting deficiencies in conventional single-substance risk evaluation frameworks. Living organisms in their natural habitats face continuous exposure to diverse chemical combinations, which frequently result in interactive effects, including synergism and antagonism, that diverge from the straightforward additive outcomes anticipated by traditional toxicological approaches. Research using animal and aquatic experimental models has shown that these exposures depend on numerous variables, such as the specific chemicals involved, their dose relationships, duration of contact, measured biological outcomes, and underlying mechanistic processes. This review examines fundamental methodological frameworks, particularly concentration addition (CA) and independent action (IA) models, used for predicting mixture toxicity, with most mixture effects falling within a two-fold range of additivity predictions though important deviations occur. Additional complicating factors include the timing of exposure and the specific biological traits of test species. The present review also addresses difficulties in applying findings from animal research to human populations, given differences in toxicokinetic processes and genetic makeup across species. To navigate these complexities, this review supports the adoption of mechanism-based frameworks incorporating high-throughput omics technologies, computational approaches, and standardized protocols for evaluating environmentally realistic mixtures. The review advocates for implementing tiered, cumulative risk-assessment methodologies that accurately represent real-world exposure conditions and emphasize protection of susceptible populations. This transformation is vital for advancing predictive toxicology and strengthening protections for public and environmental health. Ultimately, the review argues for moving beyond the obsolete single-substance paradigm toward comprehensive, evidence-driven approaches equipped to handle the multifaceted nature of chemical exposures. This review critically evaluates experimental animal studies in chemical mixture toxicology, emphasizing the complexities and prospects of applying animal findings to human health risk assessment. It identifies key gaps linking controlled experiments with epidemiological data and proposes research directions to advance risk evaluation and management of real-world chemical co-exposures.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154372"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769309","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":"Hexavalent chromium induced autophagy-dependent mTOR expression mediated by upregulation of HMGA2","authors":"Li Li ,&nbsp;Meng Dan ,&nbsp;Shengnan Li,&nbsp;Xiaojing Cui,&nbsp;Shibo Bao,&nbsp;Shengxiang Luo,&nbsp;Jun Cao","doi":"10.1016/j.tox.2025.154368","DOIUrl":"10.1016/j.tox.2025.154368","url":null,"abstract":"<div><div>High mobility group A2 (HMGA2) overexpression is often observed in cancers. Previously, we found that HMGA2 contributed to hexavalent chromium [Cr (VI)]-mediated autophagy. In this study, interestingly, Cr (VI) treatment triggered both autophagy and the mammalian target of rapamycin (mTOR) <em>in vivo</em> ( BALB/c mice, 0.5 and 1.5 mg/kg, p.o.) and <em>in vitro</em> (0.1, 0.2 and 0.4 μM in A549 and HELF cells), and both autophagy and mTOR were implicated in Cr (VI)-initiated cell growth. Autophagy and mTOR were both significantly induced by HMGA2 overexpression <em>in vivo</em> (BALB/c mice were intratracheal injected with 10 μg and 20 μg pcDNA3.1-HMGA2 plasmid complexes) and <em>in vitro</em> (A549 and HELF cells). Using the autophagy suppressor, 3-methyladenine (3MA, 2 mM), chloroquine (CQ, 10 μM), and knockdown of autophagy-related protein 4 homolog B (<em>ATG4B</em>) gene by siRNA, it was shown that Cr (VI)-provoked mTOR was reliant on autophagy. Furthermore, the results of the scratch assay indicated that HMGA2-mediated cell migration depends on autophagy, mTOR, and glycolysis. Chromatin immunoprecipitation assay elucidated elective binding of HMGA2 protein to the <em>ATG4B</em> promoter region, but not <em>AKT1</em> and <em>mTOR</em>. Altogether, our findings demonstrated that both autophagy and mTOR could be induced by Cr (VI) and they were involved in Cr (VI)-caused cell growth and migration. HMGA2 mediated this effect by transcription regulation of <em>ATG4B</em>. These suggested that blocking the HMGA2-autophagy-mTOR axis could serve as an effective strategy to inhibit Cr (VI)-induced cell viability.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154368"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744605","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":"2,4,6-triiodophenol induces glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis","authors":"Tingting Miao ,&nbsp;Shubiao Zou ,&nbsp;Binwu Xu ,&nbsp;Zisu Deng ,&nbsp;Mengjiao Di ,&nbsp;Houqun Ying","doi":"10.1016/j.tox.2025.154361","DOIUrl":"10.1016/j.tox.2025.154361","url":null,"abstract":"<div><h3>Objective</h3><div>2,4,6-Triiodophenol (TIP) is a highly toxic iodinated disinfection byproduct that is generated during water disinfection, and TIP is widely detected in drinking water. This study aimed to investigate the nephrotoxicity of TIP and its potential mechanisms.</div></div><div><h3>Materials and Methods</h3><div>An <em>in vitro</em> exposure model was constructed by using mouse glomerular mesangial cells (MES-13 cell line). The cytotoxicity of TIP was evaluated via the CCK-8 assay and microscopic morphological observation. The expression of inflammatory cytokines was detected by qRT-PCR and ELISA. Oxidative stress markers, including malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), were detected using ELISA, and cell apoptosis was analyzed by flow cytometry.</div></div><div><h3>Results</h3><div>TIP exhibited obvious dose-dependent cytotoxicity in MES-13 cells. Low concentrations of exposure showed no significant cytotoxicity, whereas high concentrations of exposure markedly inhibited cell viability. Moreover, TIP can promote the gene and protein expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). However, while the gene expression of the anti-inflammatory cytokine IL-10 was increased, its protein expression level showed no significant change, suggesting a post-transcriptional regulation or a protein translation delay effect. Further studies revealed that TIP not only overactivates oxidative stress but also induces aberrant apoptotic regulation. This finding indicates that MES-13 cells may respond to TIP-induced damage by regulating oxidative stress and cell apoptosis.</div></div><div><h3>Conclusions</h3><div>This study firstly demonstrated that TIP can induce glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis. Our findings not only provide experimental evidence to elucidate the nephrotoxic mechanisms of TIP but also contribute to establishing relevant strategies for health risk prevention and control.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154361"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649379","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":"Ophthalmotoxicology of polyhalogenated compounds","authors":"Maxime Louzon ,&nbsp;Christophe Chiquet ,&nbsp;Mohamed Kamel ,&nbsp;Lotfi Aleya ,&nbsp;Hugo Blanc ,&nbsp;Adrien Blanc","doi":"10.1016/j.tox.2025.154337","DOIUrl":"10.1016/j.tox.2025.154337","url":null,"abstract":"<div><div>Polyhalogenated compounds (PHCs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and per- and polyfluoroalkyl substances (PFAS), are persistent organic pollutants that bioaccumulate in tissues and are increasingly recognized as threats to human health. While their neurotoxic and endocrine-disrupting effects are often described, their potential impact on the ocular system remains underexplored. However, recent evidence suggests that chronic PHC exposure may contribute to a spectrum of ocular pathologies, such as retinal degeneration, cataracts and retinoblastoma. To clarify these emerging risks, this review synthesizes findings at the intersection of toxicology, ophthalmology, and environmental health, highlighting mechanistic insights into how PHCs impair ocular function. Epidemiological studies linking environmental contaminant exposure to visual deficits are discussed alongside experimental data from animal models and <em>in vitro</em> systems, with a particular focus on oxidative stress, mitochondrial dysfunction, endocrine disruption, and altered retinoid signaling as plausible pathways mediating PHC-induced visual toxicity. Given the widespread nature of PHC exposure and the increasing global burden of visual impairment, further research and regulatory oversight are urgently needed to bridge the gap between environmental toxicology and ocular health, ultimately aiming to better understand and mitigate the visual risks posed by these persistent pollutants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154337"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530476","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":"Combined exposure to polystyrene nanoplastics and bisphenol A results in mitochondrial damage and ferroptosis via the PI3K-AKT signaling pathway in mice kidneys","authors":"Qimeng Wang ,&nbsp;Yinghui Wang ,&nbsp;Ying Wang ,&nbsp;Shan Li ,&nbsp;Xue Yang ,&nbsp;Xiangchun Liu ,&nbsp;Jingyan Yang ,&nbsp;Ziying Min ,&nbsp;Shutong Liu ,&nbsp;Gang Liu","doi":"10.1016/j.tox.2025.154341","DOIUrl":"10.1016/j.tox.2025.154341","url":null,"abstract":"<div><div>Nanoplastics (NPs), a growing environmental concern, can act as carriers for co-pollutants like bisphenol A (BPA). Consequently, understanding the combined toxicity of these pollutants is critical, as mammals are often exposed to multiple environmental contaminants simultaneously, however, the potential adverse effects of NPs and/or BPA remain inadequately defined. Therefore, we conducted a six-week toxicity study in mice to evaluate the impacts of BPA, polystyrene nanoplastics (PS-NPs), and their combination. Our results demonstrated that simultaneous exposure to BPA and PS-NPs significantly worsened growth-related toxicity and induced renal damage compared to individual exposures or controls. Mechanistically, co-exposure to BPA and PS-NPs markedly elevated renal malondialdehyde concentrations while significantly reducing the activities of catalase, superoxide dismutase and glutathione peroxidase. This oxidative imbalance led to the dysregulation of the mitochondrial antioxidant system and disruption of ferroptosis kinetics <em>via</em> inhibition of the PI3K/AKT signaling pathway. In conclusion, this study demonstrated the significantly enhanced nephrotoxicity of co-exposure to PS-NPs and BPA in mice, providing crucial mechanistic insights into the toxicological interactions between NPs and endocrine disruptors in mammals. These findings highlight the potential health risks posed by multi-pollutant exposures in the real world.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154341"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145546816","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":"Characterising a HepaRG liver microphysiological system for individual bile acid secretion and chemical induced disruptions","authors":"Katharina S. Nitsche ,&nbsp;Paul L. Carmichael ,&nbsp;Wouter Bakker ,&nbsp;Hans Bouwmeester ,&nbsp;Iris Müller","doi":"10.1016/j.tox.2025.154364","DOIUrl":"10.1016/j.tox.2025.154364","url":null,"abstract":"<div><div>Liver microphysiological systems (MPS) have gained increasing attention as human-relevant models for chemical safety assessments, particularly for studies with defined endpoints, such as cholestatic injury. In this study, we built upon a previously established HepaRG-based liver MPS model using the OrganoPlate® 3-lane system. Our aim in this proof-of-concept study was to characterise the synthetic capacity and metabolic function, focusing on the bile acid secretion, under both basal and chemically treated conditions at three independent time points. Undifferentiated HepaRG cells were seeded into the perfusion channels coated with Matrigel and cultured under flow condition without the addition of dimethyl sulfoxide (DMSO). We monitored cell self-organisation, health, and maturation using microscopy, viability assays, albumin and individual bile acid secretion profiling, and gene expression analysis. To assess the metabolic competence and treatment responses regarding the bile acid secretion, the cells were exposed to rifampicin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 48 h. Despite the absence of DMSO supplementation, HepaRG cells self-organised into maturing aggregates and demonstrated inducible CYP1A2 and CYP3A4 activity by day 3. Although the synthetic capacity was generally low, the model secreted all primary (conjugated) bile acids and exhibited clear time-dependent changes in the bile acid composition under treatment. These proof-of-concept findings highlight the potential of flow conditions to enable <em>in situ</em> HepaRG maturation and represent a promising step toward defining a potential context of use as a tool for cholestatic injury.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154364"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688192","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":"Mediating roles of oxidative stress and nuclear factor kappa B signaling in benzyl butyl phthalate-aggravated allergic asthma","authors":"Fan Lei,&nbsp;Runqing Xue,&nbsp;Jianli Gu,&nbsp;Meng Zhang,&nbsp;Qing Wu,&nbsp;Yilin Gong,&nbsp;Chongyao Li","doi":"10.1016/j.tox.2025.154317","DOIUrl":"10.1016/j.tox.2025.154317","url":null,"abstract":"<div><div>It has been proposed that benzyl butyl phthalate (BBP) exposure raises the risk of allergic asthma, but current research evidence is not sufficient to fully support this claim. Examining the function and mechanism of BBP in exacerbating allergic asthma was the goal of this investigation. To create an allergic asthma model, 90 male Balb/c mice were randomly split into 6 groups, comprising of saline (control); OVA; 10 BBP + OVA; 100 BBP + OVA; 250 BBP + OVA; and 1250 BBP + OVA. To investigate if BBP makes allergic asthma worse in mice given OVA, we first examined lung histological sections and airway hyperresponsiveness (AHR). Second, we investigated oxidative stress, the signaling pathway of nuclear factor kappa B (NF-κB), and the inflammatory factors that are downstream of it to explore mechanism of BBP exacerbating allergic asthma.The results showed that, the enhanced pause (Penh) value in BBP + OVA group was remarkably greater in contrast to OVA group, indicating increased AHR, whereas worsening airway remodeling was observed in lung tissue slices. Both Penh and airway remodeling worsened as the BBP dose increased. In addition, exposure to BBP + OVA resulted in enhanced levels of markers related to the NF-κB signaling pathway and oxidative stress, decreases in Th1 inflammatory cytokine levels, and increases in Th2/Th17 inflammatory cytokine levels. Combined exposure to OVA and BBP worsened AHR and airway wall remodeling, and these impacts were correlated with oxidative stress and elevated secretion of IgE, NF-κB biomarkers, and Th1/Th2/Th17 cytokines. Therefore, we suggest that the primary mechanisms by which BBP aggravates allergic asthma through Th1/Th2/Th17 cytokine modulation include the NF-κB pathway and oxidative stress. It may be a potential drug target for the treatment of allergic asthma.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154317"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329841","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":"Real-life organochlorine mixture-induced lipid dysregulation and oxidative stress in Leydig TM3 cells: Mechanistic insights into male reprotoxicity","authors":"Ishita Virmani,&nbsp;Eliška Sychrová,&nbsp;Eliška Řehůřková,&nbsp;Darshak Gadara,&nbsp;Zdeněk Spáčil,&nbsp;Jiří Novák,&nbsp;Iva Sovadinová","doi":"10.1016/j.tox.2025.154332","DOIUrl":"10.1016/j.tox.2025.154332","url":null,"abstract":"<div><div>Persistent environmental pollutants such as organochlorines (OCs) remain a global concern due to their widespread distribution, bioaccumulative nature, and endocrine-disrupting potential. While associations with male reproductive toxicity are well documented, the underlying mechanisms, particularly those involving lipid metabolism in testicular cells, are not fully understood. This study investigates the mechanistic basis of male reprotoxicity induced by a real-life OC mixture (OC-MIX), modeled after the contaminant profile of ringed seal blubber and comprising 20 environmentally relevant OCs, including pesticides (e.g., dichlorodiphenyltrichloroethane) and industrial compounds (e.g., polychlorinated biphenyls). We applied a mechanistic <em>in vitro</em> test battery that combines receptor-specific reporter gene assays with functional profiling in immature murine Leydig TM3 cells exposed to OC-MIX concentrations ranging from 0.04 to 50 µg/mL. OC-MIX exhibited strong antiandrogenic and dioxin-like activities. Functional assays revealed reduced testosterone and progesterone levels, increased oxidative stress, and impaired mitochondrial function. These effects were driven by broad lipid dysregulation, including enhanced fatty acid degradation and acylcarnitine depletion, which was evident even at the lowest tested concentration (2.5 µg/mL). These lipid alterations were not primarily mediated via androgen receptor antagonism or aryl hydrocarbon receptor agonism. Instead, the lipidomic signature closely resembled that of the lipotoxic drug amiodarone, rather than a non-cytotoxic fatty acid mixture. Our findings underscore the central role of lipid metabolism in testicular function and demonstrate that OC-MIX exerts reproductive toxicity via complex, non-classical endocrine mechanisms. This study highlights the value of integrating lipidomics with mechanistic <em>in vitro</em> models to assess the reproductive toxicity of environmental chemical mixtures.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154332"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145453002","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":"Mechanistic insights into the structure–toxicity relationship of α-aminononanophenone derivatives: Role of CYP3A4 and oxidative stress","authors":"Yoshifumi Morikawa ,&nbsp;Nozomi Azuma ,&nbsp;Yuji Sakai ,&nbsp;Saeka Tsuchimura ,&nbsp;Hidetoshi Miyazono ,&nbsp;Koichi Suenami ,&nbsp;Emiko Yanase ,&nbsp;Satoshi Endo ,&nbsp;Akira Ikari ,&nbsp;Toshiyuki Matsunaga","doi":"10.1016/j.tox.2025.154333","DOIUrl":"10.1016/j.tox.2025.154333","url":null,"abstract":"<div><div>Continuous abuse and overdose of aminophenone derivatives, a representative group of synthetic cathinones, are known to exhibit severe damage against neuronal cells, whereas little is known about their structure–toxicity relationship and cytotoxic mechanisms. Here, we newly synthesized eight α-aminononanophenone (ANP) derivatives bearing various <em>N</em>-alkyl side chains and measured sensitivity to toxicity elicited by treatment with the derivatives using six human cell lines. The sensitivity assay revealed a positive correlation between the length of substituted <em>N</em>-alkyl side chain and the strength of cytotoxicity of the ANP derivatives in all cell lines. In addition, treatment with butyl-ANP (B-ANP), one of the most potent cytotoxic ANP derivatives, markedly induced overproduction of reactive oxygen species (ROS) and 4-hydroxy-2-nonenal, mitochondrial membrane dysfunction and caspase-3/9 activation in neuronal SK-N-SH cells. Furthermore, the treatment resulted in the reductions of antioxidant capacity and 26S proteasome-based proteolytic activities and the significant formation of aggresome. These results indicate that exposure to the ANP derivatives provokes neuronal cell apoptosis through ROS overproduction and lowering of antioxidant properties. A measurement of ANP derivatives by liquid chromatography/mass spectrometry/mass spectrometry analysis revealed that cytochrome P450 (CYP) 3A4 metabolizes ANP derivatives with short <em>N</em>-alkyl chains (methyl and ethyl groups) in preference to ones with longer <em>N</em>-alkyl side chains (propyl and butyl groups) in liver HepG2 cells. Additionally, pretreatment with a CYP3A4 inhibitor augmented the cytotoxicity elicited by diethyl-ANP, not B-ANP. Therefore, it is inferred that CYP3A4-mediated metabolism is also a key factor involved in the reduction of neurotoxicity of ANP derivatives.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154333"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534749","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}