Toxicology letters最新文献

{"title":"Study on the effect and mechanism of PM2.5 on the expression of Alzheimer’s disease-like pathological proteins in SH-SY5Y cells","authors":"Huiwen Kang ,&nbsp;Chenyang Si ,&nbsp;Xuan Shang ,&nbsp;Qian Song ,&nbsp;Wenli Zhang ,&nbsp;Jinlong Li ,&nbsp;Shoufang Jiang","doi":"10.1016/j.toxlet.2025.04.014","DOIUrl":"10.1016/j.toxlet.2025.04.014","url":null,"abstract":"<div><div>Fine particulate matter (PM_2.5) is recognized as one of the most harmful environmental pollutants to human health. Current research indicates that PM_2.5 exhibits neurotoxic effects, though the specific mechanisms remain unclear. In this study, SH-SY5Y cells were exposed to PM_2.5 (100 μg/mL for 24 h) to observe its effects on the expression of Alzheimer's disease (AD)-related proteins and explore the possible mechanisms of central nervous system injury caused by PM_2.5. Based on bioinformatics results, the study employed a PI3K inhibitor (LY294002, 10 μmol/L for 1 h) and a reactive oxygen species (ROS) inhibitor, N-acetyl-L-cysteine (NAC, 5 nmol/L for 1 h), as interventions. The results demonstrated that PM_2.5 exposure significantly intensified oxidative stress in SH-SY5Y cells, upregulated the expression of inflammatory factors, and increased apoptosis. Additionally, exposure to PM_2.5 led to elevated levels of AD-related pathological proteins, including amyloid-β (Aβ), and promoted Tau phosphorylation, further indicating its potential neurotoxic effects. Furthermore, the ROS/PI3K/Akt/GSK-3β pathway was found to play a key role in these processes. This research provides a basis for understanding the impact of PM_2.5 on Alzheimer’s disease patients and offers recommendations for the prevention of haze-related health risks, as well as for risk management by relevant governmental departments.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 109-120"},"PeriodicalIF":2.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942782","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":"Toxic effects of malachite green on plant and animal models: A study on root growth inhibition, hematological changes, histopathology, and molecular analysis","authors":"Rubait Hasan ,&nbsp;Md. Mahmudul Hasan ,&nbsp;Jamiatul Husna Shathi ,&nbsp;Esraa Tamam ,&nbsp;Amaal E. Ahmed ,&nbsp;Ariful Haque ,&nbsp;Zahidur Rahmann ,&nbsp;Md Tariqul Islam ,&nbsp;Md. Abu Reza ,&nbsp;Mohammad Shahangir Biswas ,&nbsp;Kazi Md. Faisal Hoque","doi":"10.1016/j.toxlet.2025.05.003","DOIUrl":"10.1016/j.toxlet.2025.05.003","url":null,"abstract":"<div><div>Malachite green (MG), a suggestive chemical for tumor development and carcinogenicity, is widely used as an illicit food coloring agent, posing risks to consumers and handlers. This study aimed to assess the toxic effects of MG in both plant and animal models. Different doses of MG (375, 750, and 1500 mg/L) were applied for 24 h to evaluate root growth inhibition, mitotic index (MI), and chromosomal aberrations in <em>Allium cepa</em> L. roots for genotoxicity analysis. In animal studies, forty Swiss albino mice were divided into four groups: control and three treatment groups, which were orally administered MG at 375 (low), 750 (medium), and 1500 (high) mg/kg body weight for 13 weeks. Hematological, biochemical, histopathological, and molecular analyses were performed on liver, kidney, and intestinal tissues post-treatment. MG significantly reduced root length and MI in <em>A. cepa</em> roots dose-dependently causing chromosomal abnormalities. MG treatment significantly lowered the body weights of mice and increased platelet, monocyte, and white blood cell counts, while reducing hemoglobin, hematocrit, and red blood cell counts. Serum analysis showed elevated ALT, ALP, AST, bilirubin, creatinine, and urea, indicating hepatotoxicity and nephrotoxicity. Histopathological examination revealed vacuolation, congestion, and inflammatory infiltration in the liver, glomerular shrinkage, tubular degeneration, and interstitial edema in the kidney, and epithelial sloughing, submucosal necrosis, and inflammatory infiltration in the colon. RT-qPCR analysis demonstrated increased Bcl-2, Beclin-1, and NF-κB mRNA expression with decreased Bax mRNA. These findings suggest MG is a potent genotoxic and carcinogenic agent even at lower doses threatening human health.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 61-73"},"PeriodicalIF":2.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936858","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":"NR1D1 mitigates IL-17a-induced small airway remodeling in biomass smoke-induced COPD","authors":"Lizhi Huang ,&nbsp;Juan Xu ,&nbsp;Hongbin Zhou ,&nbsp;Haiqing Li ,&nbsp;Weitao Cao ,&nbsp;Jinding Pu","doi":"10.1016/j.toxlet.2025.05.002","DOIUrl":"10.1016/j.toxlet.2025.05.002","url":null,"abstract":"<div><h3>Introduction</h3><div>Biomass smoke (BS) exposure is a critical environmental risk factor for Chronic Obstructive Pulmonary Disease (COPD). In this study, mechanisms of biomass smoke (BS)-induced small airway disease are explored, with a focus on the roles of Interleukin-17a (IL-17a) and Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1).</div></div><div><h3>Methods</h3><div>This study included 20 BS exposure COPD (BS-COPD) patients and 13 controls, who underwent chest high-resolution computed tomography (HRCT) scans to assess emphysema and small airway disease. The control group was divided into a low- and high BS exposure control group. Serum IL-17a levels were measured. Wild-type and IL-17a-/- B6/C57 mice were exposed to wood smoke to establish a COPD model in mice. Airway pathology was evaluated by histological analysis. The effects of IL-17a and NR1D1 on cell proliferation of BEAS-2b cells exposed to wood smoke particulate matter 2.5 were assessed in vitro using flow cytometry and Western blotting.</div></div><div><h3>Results</h3><div>HRCT revealed significantly higher small airway disease and emphysema in BS-COPD patients compared to controls (p &lt; 0.01). Small airway disease exhibited the strongest negative correlation with FEV1%predicted (r = -0.61, p = 0.004). High-exposure control group showed significant BS Index correlations with small airway disease (r = 0.81, p = 0.049) and emphysema (r = 0.87, p = 0.025). Serum IL-17a levels correlated with small airway disease in BS-COPD (r = 0.48, p = 0.033). The mouse model demonstrated higher airway wall thickness and small airway disease in IL-17a-/- mice exposed to wood smoke. In vitro, IL-17a promoted BEAS-2b cell proliferation, an effect enhanced by NR1D1 downregulation.</div></div><div><h3>Conclusions</h3><div>BS exposure drives emphysema and small airway disease in non-COPD individuals. NR1D1 downregulation exacerbates IL-17a–mediated remodeling in vitro, suggesting therapeutic potential.</div></div><div><h3>Trial registration</h3><div>ChiCTR-OOC-16008692</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 74-86"},"PeriodicalIF":2.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936859","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":"Impact of skin temperature and intradermal pH on transdermal fluoride absorption following hydrofluoric acid exposure: An ex vivo diffusion cell study in human skin","authors":"Suvarna Mini Vijayan ,&nbsp;Anna Wolfschmidt ,&nbsp;Thomas Göen ,&nbsp;Raymund E. Horch ,&nbsp;Ingo Ludolph ,&nbsp;Hans Drexler ,&nbsp;Sonja Kilo","doi":"10.1016/j.toxlet.2025.05.005","DOIUrl":"10.1016/j.toxlet.2025.05.005","url":null,"abstract":"<div><div>Accidents involving hydrofluoric acid (HF) can cause systemic poisoning due to the transdermal absorption of fluoride ions. The present study investigates the impact of skin temperature and intradermal pH on fluoride absorption and its kinetics. Human skin was exposed to 30 % HF for 3 minutes using a static diffusion cell model. The study compared cumulative fluoride absorption at two different skin temperatures (24°C and 32°C) and two intradermal pH values (6.5 and 7.2). Experiments were performed at least three times per treatment and per donor (n = 5), over a duration of 8 h and 12 h for pH and temperature experiments, respectively. Results showed that fluoride absorption increased with temperature, with a ∼17.8 % increase in cumulative penetration at 32°C compared to 24°C. The maximum flux rate through the skin was reached within the first hour and was ∼54 % lower at 24°C. Additionally, acidifying the skin to an intradermal pH of 6.5 led to a significant increase in cumulative fluoride absorption by ∼12.6 % and a ∼50.3 % increase in the maximum flux rate. The findings suggest that reducing fluoride absorption after accidental skin contact with HF may be achieved by lowering skin temperature and buffering intradermal pH to a physiological level. These results have important implications for first-aid measures in real-life scenarios involving HF exposure. Controlling skin temperature by cooling and intradermal pH with the addition of buffering agents may enhance decontamination strategies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 87-96"},"PeriodicalIF":2.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942780","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":"Copper exposure at a daily dose twice the recommended in diabetic rats induces oxidative stress, vascular dysfunction and perivascular adipose tissue inflammation in diabetic rats","authors":"Julia Antonietta Dantas da Silva ,&nbsp;Filipe Martinuzo Filetti ,&nbsp;Natália Pimentel da Silva ,&nbsp;Karoline Neumann Gomes ,&nbsp;Jones Bernardes Graceli ,&nbsp;Andressa Bolsoni Lopes ,&nbsp;Dalton Valentim Vassallo ,&nbsp;Karolini Zuqui Nunes","doi":"10.1016/j.toxlet.2025.05.004","DOIUrl":"10.1016/j.toxlet.2025.05.004","url":null,"abstract":"<div><div>Individuals with diabetes often have a heightened risk of cardiovascular diseases and present copper (Cu) metabolism imbalances. We investigated the effect of chronic exposure to twice the recommended daily dose of CuCl₂ on vascular reactivity in isolated thoracic aorta segments of diabetic and non-diabetic rats. Eighty male Wistar rats, aged 12 weeks, were divided into four groups: Control (Ct), Copper (Cu), Diabetes Mellitus (DM), and Diabetes + Copper (DM+Cu). Type 1 diabetes was induced using a single dose of streptozotocin (65 mg/kg i.p), and the animals exposed to Cu received twice the recommended daily dose (25.7 µg/Kg/day CuCl₂) for 30 days. After treatment, we investigated vascular reactivity and performed histological evaluations on samples of aortas and perivascular adipose tissue (PVAT). Our findings revealed pronounced weight loss and higher hyperglycemia in the DM+Cu group compared to DM, along with increased pro-inflammatory factors in PVAT (IL-6). Vascular reactivity to phenylephrine decreased without PVAT, accompanied by elevated vasodilator factors: NO and H₂O₂, and involvement of K+ channels. Additionally, we observed an increase in the thickness of the aorta wall, collagen deposition. In the presence of PVAT, vascular reactivity increased in the DM+Cu and Cu groups. These findings demonstrate that exposure to double the recommended Cu dose in diabetic animals leads to endothelial and PVAT dysfunction, associated with elevation of vasodilator and pro-inflammatory factors.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 97-108"},"PeriodicalIF":2.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942781","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 Alarming Consequences of Workforce Reductions at the FDA, EPA, NIH and CDC in the United States","authors":"Martin van den Berg PhD (Editor-in-Chief, Regulatory Toxicology & Pharmacology and Current Opinion in Toxicology) ,&nbsp;Daniel R. Dietrich PhD (Editor-in-Chief, Chemico-Biological Interactions, Computational Toxicology, and Journal of Toxicology and Regulatory Policy) ,&nbsp;Sonja von Aulock PhD (Editor-in-Chief, ALTEX – Alternatives to Animal Experimentation) ,&nbsp;Anna Bal-Price PhD (Editor-in-Chief, Reproductive Toxicology) ,&nbsp;Michael D. Coleman PhD (Editor-in-Chief, Environmental Toxicology and Pharmacology) ,&nbsp;Mark T.D. Cronin PhD (Editor-in-Chief, Computational Toxicology) ,&nbsp;Paul Jennings PhD (Editor-in-Chief, Toxicology in Vitro) ,&nbsp;Angela Mally PhD (Editor-in-Chief, Toxicology Letters) ,&nbsp;Mathieu Vinken PhD (Editor-in-Chief, Toxicology and NAM Journal) ,&nbsp;Matthew C. Wright PhD (Editor-in-Chief, Food and Chemical Toxicology)","doi":"10.1016/j.toxlet.2025.05.001","DOIUrl":"10.1016/j.toxlet.2025.05.001","url":null,"abstract":"","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 30-31"},"PeriodicalIF":2.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908083","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":"Studies on acute dermal toxicity and dermal absorption of a nanoform zinc oxide (ZnO; NM-111) in rats","authors":"Tanja Hansen ,&nbsp;Thomas Tillmann ,&nbsp;Karin Wiench ,&nbsp;Otto Creutzenberg","doi":"10.1016/j.toxlet.2025.04.011","DOIUrl":"10.1016/j.toxlet.2025.04.011","url":null,"abstract":"<div><div>In two studies, the dermal toxicity (limit test following OECD TG 402) and toxicokinetics (with [⁶⁵Zn]-tagged ZnO following OECD TG 427) of a nanostructured ZnO particle were characterized. The overall aim was to assess the risk of its systemic availability. Wistar rats were dermally treated once with 2000 mg ZnO/kg b.w. (limit test). – Male rats were treated topically with 2 mg/cm^{2 65}ZnO for 6 h. Necropsy was done after the end of the exposure period (6 h) and after 24 and 72 h to investigate dermal absorption of ⁶⁵ZnO. ZnO showed no clinical signs of toxicity in the limit test. – ⁶⁵ZnO was not significantly absorbed following deposition: In the group means, 62–76 % of the dose applied were recovered in the not absorbed fraction. The amount of ⁶⁵ZnO in the <em>stratum corneum</em> was found to be approx. 15 %, 8 % and 4.6 % after 6, 24 and 72 h, respectively. The ⁶⁵ZnO content in the remaining skin at the application site (viable skin + remaining <em>stratum corneum</em>) accounted for approx. 10 %, 16 % and 16 % after 6, 24 and 72 h (total on/in the skin 25 %, 24 % and 20.6 % after 6, 24 and 72 h). No relevant radioactivity was found in faeces, urine, cage wash, organ or tissue samples.</div><div>The acute dermal limit test with ZnO resulted in ‘Unclassified’ (globally harmonized system). – Radioactivity, representative of ⁶⁵ZnO, was not detected systemically after dermal application. Overall, the results indicate that ⁶⁵ZnO was not absorbed with subsequent translocation beyond the skin into the blood compartment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 42-49"},"PeriodicalIF":2.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924041","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":"In silico and in vitro analysis of the genotoxic and mutagenic potential of STING modulators","authors":"Santosh Vishwakarma,&nbsp;Saketh S. Dinavahi,&nbsp;Kapil R. Nikam,&nbsp;Bibhuti Ranjan,&nbsp;Ramesh Rangaiah,&nbsp;M. Karunyaa,&nbsp;Anupreetha V,&nbsp;Arul Ramakrishnan,&nbsp;Saravanakumar Dhakshinamoorthy","doi":"10.1016/j.toxlet.2025.04.012","DOIUrl":"10.1016/j.toxlet.2025.04.012","url":null,"abstract":"<div><div>The STING pathway plays a crucial role in dsDNA homeostasis and has been implicated in several diseases, including cancer and autoimmune disorders. Consequently, efforts have been made to develop modulators (agonists and antagonists) of the STING pathway. However, it is imperative to clinically evaluate the mutagenic and genotoxic potential effects of these novel molecules. For this purpose, an exhaustive list of STING modulators was subjected to knowledge- and expert-based <em>in silico</em> mutagenicity evaluations. A few antagonists were predicted to be positive for mutagenicity by Derek, and a few agonists were predicted to be positive (moderate reliability) by Vega. Based on the varying results of the computational approaches (Derek and Vega) for prediction of mutagenicity, two of each STING agonists and antagonists were evaluated using the bacterial reverse mutation test (Ames test; with and without metabolic activation) at concentrations of 1.935–250 μg/well. Additionally, the compounds (5, 10, and 20 μM) were subjected to single-cell gel electrophoresis (comet) assay to evaluate DNA damage in HepG2 cells. <em>In silico</em> analysis predicted that multiple STING modulators are mutagenic. In addition, the Ames test results demonstrated that only C-178, a STING antagonist, is mutagenic, while the other antagonist (SN-001) and both agonists (CMA and SR-717) are not mutagenic at the concentrations evaluated. C-178 is mutagenic, even without metabolic activation. Although not significantly different, there was a dose-dependent increase in comet tail length with C-178, thereby confirming genotoxicity, even in mammalian cells. The other STING modulators were inactive as per the comet assay. In summary, although mutagenic potential is not chemical class-specific, our findings highlight the carcinogenic potential of STING modulators, such as the covalent binder C-178. Caution must be exercised when developing novel STING modulators to avoid toxicological liabilities. Additionally, knowledge- and expert-based <em>in silico</em> evaluation of mutagenicity could help quickly identify toxicological potential.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 21-29"},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890877","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":"Enhanced toxic effects of photoaged microplastics on the trophoblast cells","authors":"Yan Zhang ,&nbsp;Zijie Zhou ,&nbsp;Xiaoli Wang ,&nbsp;Shouhai Jiao ,&nbsp;Qingshan Zhang ,&nbsp;Shuai Bao ,&nbsp;Shuping Zhang ,&nbsp;Li Sun ,&nbsp;Xiaolu Li","doi":"10.1016/j.toxlet.2025.04.010","DOIUrl":"10.1016/j.toxlet.2025.04.010","url":null,"abstract":"<div><div>Microplastics (MPs) are emerging as a novel pollutant, raising significant concerns regarding their adverse effects on human health. Furthermore, MPs are susceptible to light-induced aging in the environment, which alters their physical characteristics and potentially alters their toxic effects. While previous studies have documented the retention of MPs in the placenta, the specific impacts of MPs, particularly aged MPs, on placental function remain poorly understood. In the current study, we utilized 1 µm polystyrene microplastics (PS-MPs), a widely used model for MPs, to evaluate the effects of photoaged MPs on the placenta. Following oral administration of PS-MPs beginning on embryonic day 3.5 (E3.5), we observed impaired fetal growth and damage to the placental labyrinth chorionic layer in the treated pregnant mice by embryonic day 13.5 (E13.5). The photoaged PS-MPs were generated by exposure to simulated lighting for 7 or 14 days, resulting in alterations to their physical properties. Notably, enhanced cytotoxicity in trophoblast cells was observed for photoaged PS-MPs compared to pristine PS-MPs. Mechanistically, the altered physical properties of PS-MPs, along with elevated lipid peroxidation, may contribute to the increased cytotoxicity of the photoaged MPs. Our findings provide new insights into the detrimental effects and underlying mechanisms of both MPs and, in particular, aged MPs on the placenta and embryonic development. These insights are crucial for assessing the risks posed by MPs to human pregnancy.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 32-41"},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917942","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 induction of quinone oxidoreductases NQO1 and NQO2 by clozapine: Potential implications for clozapine-induced agranulocytosis","authors":"Md Harunur Rashid ,&nbsp;Dinesh Babu ,&nbsp;Newton H. Tran ,&nbsp;Steven Lockhart ,&nbsp;Mohammed A. Alqahtani ,&nbsp;Mahmoud A. El-Ghiaty ,&nbsp;Ayman O.S. El-Kadi ,&nbsp;Pierre Chue ,&nbsp;Arno G. Siraki","doi":"10.1016/j.toxlet.2025.04.013","DOIUrl":"10.1016/j.toxlet.2025.04.013","url":null,"abstract":"<div><div>Clozapine exhibits superior efficacy in the management of treatment-resistant schizophrenia. However, clozapine is currently considered under-prescribed as it carries a risk of idiosyncratic drug reactions (including severe neutropenia or agranulocytosis). The mechanisms of clozapine-induced agranulocytosis mechanisms are evolving. Reports of polymorphisms with NADPH: Quinone Oxidoreductase 2 (NQO2) being associated with clozapine-induced agranulocytosis prompted the studies described herein. Clozapine is known to produce reactive, electrophilic metabolites. It is not known if the latter can interact with NQO2 or with NQO1, its more well-characterized isoform, as quinoid electrophiles do. We hypothesized that clozapine or its metabolites can induce both NQO1 and NQO2 expression via the Nrf2 signaling pathway, as observed with quinoid electrophiles. HL-60 cells were used in this study as they are similar to granulocytes/neutrophils and contain enzymes to metabolize clozapine. A UV-Vis spectrophotometric assay was performed to determine NQO1 and NQO2 enzymatic activity using selective substrates and inhibitors. Immunoblotting was used to investigate NQO1, NQO2, and Nrf2 protein expression. NQO1 and NQO2 gene expression was determined using RT-PCR. Clozapine treatment induced NQO1 and NQO2 enzyme activity, mRNA, and protein expression significantly more than vehicle control accompanied by translocation of the transcription factor, Nrf2, from cytoplasm to nucleus. A structurally related antipsychotic, quetiapine, did not show these effects. The upregulation of both NQO1 and NQO2 enzymatic activity, protein, and gene expression indicated that these enzymes may be involved in the biological response to clozapine toxicity. The translocation of the Nrf2 suggested that the Nrf2 signaling pathway is involved in these response pathways. Further studies are required to determine if NQO2 expression levels and activity are protective mechanisms against clozapine-induced agranulocytosis or if NQO2 levels are a prognostic risk factor for clozapine-induced agranulocytosis.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"409 ","pages":"Pages 50-60"},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924042","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}