Toxicology and applied pharmacology最新文献

{"title":"Kynurenine enhances aryl hydrocarbon receptor signaling and expression levels of multidrug resistance genes in head and neck squamous cell carcinoma cell lines but does not change the potency of antineoplastic drugs","authors":"Gzona Bajraktari-Sylejmani ,&nbsp;Marlene Piribauer ,&nbsp;Sven Groessl ,&nbsp;Patrick Bernhard ,&nbsp;Gerhard Dyckhoff ,&nbsp;Rolf Warta ,&nbsp;Christel Herold-Mende ,&nbsp;Dirk Theile ,&nbsp;Johanna Weiss","doi":"10.1016/j.taap.2025.117443","DOIUrl":"10.1016/j.taap.2025.117443","url":null,"abstract":"<div><div>Efficacy of the standard cytotoxic drugs against head and neck squamous cell carcinoma (HNSCC) is limited, underlining the potential relevance of multidrug resistance (MDR), mediated by drug transporters and drug-metabolising enzymes. While the major regulator of these proteins, the pregnane-X-receptor, is of minor relevance for HNSCC, little is known about the aryl hydrocarbon receptor (AhR) signaling, its transcriptional effect on MDR genes and phenotypic MDR upon activation. Using established HNSCC cell lines, AhR reporter gene assays, quantitative reverse transcription polymerase chain reaction, and proliferation assays, this study demonstrates that AhR and its major cofactors (heat shock protein 90, AhR nuclear translocator, and AhR-interacting protein 1) are expressed and that AhR is active, and druggable. The potent AhR ligand, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) increased AhR activity in these cells up to 5.4-fold and strongly induced mRNA expression of cytochrome P450 (<em>CYP) 1A1</em> (up to 224-fold) and <em>CYP1B1</em> (up to 20-fold), while breast cancer resistance protein (<em>ABCG2)</em> was hardly enhanced (up to 2.2-fold). The endogenous ligand of AhR kynurenine (2–4-fold) and its “activated” condensation product (2–250-fold) also enhanced these genes' expression levels. However, AhR activation and target gene induction were not accompanied by relevant alterations of the antiproliferative effects of docetaxel, paclitaxel, cisplatin, carboplatin, or 5-fluorouracil. Together, this data shows that AhR signaling is in fact active in HNSCC, but its therapeutic role in HNSCC is unlikely related to induction of MDR genes. In contrast, the immune system-regulating effects of kynurenine-mediated AhR activation is likely of higher relevance and thus needs further evaluation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117443"},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306236","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":"Assessing the effects of silver nanoparticles on ARPE-19 cells via high-throughput phenotypic profiling with the Cell Painting assay","authors":"Gabrielle Byrd ,&nbsp;Alice Goldstein-Plesser ,&nbsp;Jo Nyffeler ,&nbsp;Clinton M. Willis ,&nbsp;Anna Fisher ,&nbsp;William K. Boyes ,&nbsp;Joshua A. Harrill","doi":"10.1016/j.taap.2025.117444","DOIUrl":"10.1016/j.taap.2025.117444","url":null,"abstract":"<div><div>Increasing commercialization of silver nanoparticles (AgNPs) has resulted in elevated opportunity for human exposure and outpaced traditional risk assessment approaches that rely on in vivo testing. Therefore, efficient methods are needed to evaluate potential hazards of AgNPs. Previous studies identified particle size and surface charge as determinants of AgNP toxicity, which has primarily been attributed to reactive oxygen species generation. Those studies have generally focused on cytotoxicity or targeted cellular effects, potentially missing critical sub-cytotoxic effects. Here, high throughput phenotypic profiling (HTPP) with the Cell Painting assay was used to characterize the effects of 12 distinct AgNPs (≤ 30 μg/mL) on organelle morphology in human retinal pigmented epithelial cells (ARPE-19). Three coatings (branched polyethyleneimine, polyvinylpyrrolidone, citrate) were selected for their distinct surface charges and tested at 4 different sizes (40, 60, 80, 100 nm) to determine the effects of these properties on toxicity. HTPP was conducted in conjunction with a transcriptomic profiling experiment involving 60 nm particles of all coating types. This facilitated evaluation of mechanisms of action underlying morphological effects observed using HTPP. A cell viability and apoptosis assay was also run in parallel and used to exclude cytotoxic treatments from phenotypic and transcriptomic analyses. HTPP revealed concentration-dependent emergence of sub-cytotoxic phenotypic profiles that clustered by coating type, suggesting surface charge to be more influential than particle size in the determination of AgNP toxicity. The transcriptomic data highlighted oxidative stress and cell cycle alterations as fundamental underlying toxicity mechanisms of AgNPs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117444"},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321021","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":"Signature gene expression model for quantitative evaluation of MASH-like liver injury in mice","authors":"Volodymyr P. Tryndyak ,&nbsp;Rose A. Willett ,&nbsp;Zhuolin Song ,&nbsp;Kostiantyn Dreval ,&nbsp;Jennifer M. Hughes Hanks ,&nbsp;Mark I. Avigan ,&nbsp;Fred A. Wright ,&nbsp;Frederick A. Beland ,&nbsp;Ivan Rusyn ,&nbsp;Igor P. Pogribny","doi":"10.1016/j.taap.2025.117442","DOIUrl":"10.1016/j.taap.2025.117442","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of chronic pathologic conditions strongly associated with metabolic syndrome and affects approximately 38 % of the global population. Untreated MASLD may progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis and is currently recognized as one of the main risk factors for hepatocellular carcinoma (HCC). The molecular determinants of MASLD stratification are not clearly defined and require additional investigation. In this study, we used a dietary preclinical model of MASH-like liver injury induced by feeding male and female Collaborative Cross CC042/GeniUnc mice a high-fat and high-sucrose diet (HF/HS) for up to 60 weeks and analyzed the global hepatic transcriptomic alterations. Chronic feeding the HF/HS diet induced profound alterations in liver gene expression associated with the key toxicity pathways, including cell death, cell proliferation, inflammation, fibrosis, and hyperplasia. We identified a panel of 74 differentially expressed genes, the expression of which significantly correlated with total MASH pathology scores in the livers of both male and female mice. Using these genes, we developed a machine-learning model that accurately predicted the severity of MASH-like liver injury in several different animal models of MASH and demonstrated high accuracy for a smaller model with 37 genes. We also used this signature to analyze human gene expression data and show its translational relevance. The results of this study demonstrate that a panel of MASH-related genes can assist in the assessment of MASH-like liver injury, its monitoring, and in development of mechanism-based drugs against MASH.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117442"},"PeriodicalIF":3.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317921","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":"Repurposing FDA-approved allosteric drugs as non-competitive inhibitors of human UGTs: An integrated computational study and biochemical validation","authors":"Emadeldin M. Kamel ,&nbsp;Ali H.M. Osman ,&nbsp;Sarah I. Othman ,&nbsp;Amal Mohamad Husein Mackawy ,&nbsp;Faris F. Aba Alkhayl ,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1016/j.taap.2025.117441","DOIUrl":"10.1016/j.taap.2025.117441","url":null,"abstract":"<div><div>UDP-glucuronosyltransferases (UGTs) catalyze a major detoxification route for xenobiotics, yet chemical tools that modulate their activity are virtually absent and the possibility of allosteric regulation is largely unexplored. We combined ligand-based target prediction, structure-based docking, long-timescale molecular dynamics and MM/PBSA free-energy calculations to search the pharmacopeia for hidden UGT modulators. Six FDA-approved allosteric drugs were screened against the catalytic domains of UGT1A1, 1A9, 2B7 and 2B15. Docking and 200-ns simulations revealed a previously unrecognized cryptic pocket ∼10 Å from the catalytic histidine that stably accommodated all six ligands; ivacaftor and cinacalcet produced the deepest free-energy basins and the most favorable MM/PBSA binding energies (−35.5 and − 31.2 kcal mol⁻¹, respectively). FEL analysis showed that ligand binding funnels the enzyme's conformational ensemble into a single deep basin, providing a dynamic explanation for the <em>V</em>_max depression observed in vitro. In recombinant enzymes and pooled human-liver microsomes these two compounds inhibited glucuronidation with low-micromolar potency (IC₅₀ ≈ 3–4 μM) while the remaining drugs were an order of magnitude weaker, mirroring the computational ranking. Lineweaver–Burk and Michaelis–Menten analyses showed pure non-competitive behavior, confirming that pocket occupancy depresses <em>V</em>_max without altering <em>K</em>_m. The strong correlation between calculated ΔG_bind and experimental pIC₅₀ (ρ = 0.89) validates the predictive pipeline. Pharmacokinetic modelling suggests that clinically relevant concentrations of ivacaftor and cinacalcet may modulate UGT1A9- and UGT1A1-mediated clearance, revealing a previously unrecognized drug–drug-interaction risk. Altogether, the work delivers the small-molecule allosteric probes for UGTs, establishes a general workflow for mining existing drugs as phase-II enzyme modulators, and provides a structural framework for developing isoform-selective UGT therapeutics.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117441"},"PeriodicalIF":3.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279160","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":"Unveiling the acute toxic pathology and transcriptomic signature of ocular exposure to phosgene oxime using an in vivo mouse model: A novel pilot study.","authors":"Ebenezar Okoyeocha, Natalie Vredevoogd, Shreya Paithankar, Bryan Masino, Poojya Anantharam, Dinesh Goswami, Charlotte Madigan, Megha Suresh, Dodd Sledge, Bin Chen, Neera Tewari-Singh","doi":"10.1016/j.taap.2025.117438","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117438","url":null,"abstract":"<p><p>Phosgene oxime (CX), a toxic nettle and highly dangerous urticating vesicant, is a potential chemical threat agent. Exposure to CX is a concern due to its penetrative property, resulting in immediate damage to the skin, lungs, and eye tissues. Although the eye is the most sensitive organ to chemical exposures including CX, there is a lack of research on CX, with a knowledge gap on its toxic effects and the mechanism(s) of ocular injuries. This novel pilot study investigated the toxic pathophysiological effects of CX exposure in mouse ocular tissue. The eyeballs of C57BL/6 mice were either unexposed (sham) or exposed to CX for 15 or 30 s, and eyes were collected for assessments 24 h after exposure, following euthanasia. CX exposure caused a significant degradation of the corneal epithelial layer, increased cellularity of the corneal stroma, loss of endothelial cells, and indicated damage to the ciliary body, lens, and the retina. RNA sequencing using DESeq2 (p-value ≤0.01 and |log2-Fold Change| ≥ 1) identified 697 downregulated and 233 upregulated genes after ocular CX exposure. Functional pathway enrichment using Kyoto Encyclopedia of Genes and Genomes pathway enrichment revealed upregulation of pathways mainly related to inflammation (including cytokines) and cell death including ferroptosis, and downregulation of pathways mainly related to metabolism and tight junction, This pilot study will facilitate in designing further comprehensive studies aimed at, developing relevant CX-induced acute and delayed ocular injury models, and in identifying injury biomarkers and associated mechanisms.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117438"},"PeriodicalIF":3.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286542","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":"Phlorotannins from edible marine seaweed Ecklonia stolonifera disrupt USP5-Cav3.2 calcium channel interactions and reverse chronic inflammatory pain","authors":"Md Yousof Ali ,&nbsp;Vinicius M. Gadotti ,&nbsp;Flavia T.T. Antunes ,&nbsp;Agustin Garcia-Caballero ,&nbsp;Hyun Ah. Jung ,&nbsp;Jae Sue Choi ,&nbsp;Gerald W. Zamponi","doi":"10.1016/j.taap.2025.117440","DOIUrl":"10.1016/j.taap.2025.117440","url":null,"abstract":"<div><div><em>Ecklonia stolonifera</em> is an edible marine seaweed that contains a high amount of phlorotannins, including phlorofucofuroeckol A (PFFA) and dieckol that have a range of pharmacologic effects. Here we report that these two phlorotannins block the interactions between the deubiquitinase USP5 and the Cav3.2 T-type calcium channel which we previously identified as a unique molecular target for pain. PFFA and dieckol delivered intrathecally (10 μg/i.t.) or intragastrically (30 mg/kg, p.o.) inhibited both phases of formalin-induced nocifensive behaviors and eliminated thermal hyperalgesia in a chronic inflammatory pain model induced by administering complete Freund's adjuvant (CFA) to the hind paws of male and female mice. Dieckol but not PFFA lost its analgesic effects in Cav3.2 null mice treated with CFA, suggesting that Cav3.2 channels are not essential for the in vivo actions of PFFA, but are required for those exerted by dieckol. Overall, our results suggest that phlorotannins derived from edible marine seaweeds, particularly PFFA, could be a novel class of analgesics that target the Cav3.2/USP5 interaction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117440"},"PeriodicalIF":3.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270802","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":"DNA damage response inhibition is an early event in cadmium-induced breast carcinogenesis","authors":"Alexandra N. Nail ,&nbsp;Ashley V. Chavez ,&nbsp;Aliyah N. Bailey ,&nbsp;Mayukh Banerjee ,&nbsp;Jared L. Scott ,&nbsp;Shelia D. Thomas ,&nbsp;J. Christopher States","doi":"10.1016/j.taap.2025.117439","DOIUrl":"10.1016/j.taap.2025.117439","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with few treatment options that disproportionately affects individuals with <em>Breast Cancer 1</em> (<em>BRCA1</em>) gene mutations and young, non-Hispanic Black women. However, <em>BRCA1</em> mutation frequencies are similar among women from all races/ethnicities, with the exception of Ashkenazi Jewish women, suggesting that gene-environment interactions contribute to TNBC disparities. Environmental cadmium (Cd) exposure is positively associated with breast cancer and Cd accumulates in human breast tumors compared to normal adjacent tissue. Previous work determined that Cd exposure promotes MCF10A cell malignant transformation after 40 weeks. Here, we report that chronic Cd exposure dysregulates essential metal homeostasis and promotes significant accumulation of DNA double-strand breaks (DSBs). Moreover, phosphorylation of Breast Cancer gene 1 (BRCA1) and Tumor Protein P53 (TP53) at critical sites (pSer1524 and pSer392, respectively) required for DNA damage response (DDR) signaling were significantly reduced by chronic Cd exposure in pre-malignant MCF10A cells. We also demonstrate significantly lower cyclin dependent kinase inhibitor 1A (CDKN1A) expression and increased RB1 phosphorylation (pSer807/811), providing evidence for reduced BRCA1 and/or TP53 function in cells chronically exposed to Cd. Our results suggest that chronic Cd exposure inhibits DDR signaling both indirectly by depletion of essential metals and by inhibition of DDR zinc finger protein activation, providing novel mechanisms for environmentally-induced TNBC. As a result, our study provides a molecular mechanism that may contribute to TNBC disparities.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117439"},"PeriodicalIF":3.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286541","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 cardiac safety profile of drugs and their potential to induce clinical cardiotoxicity","authors":"Bernard Christophe","doi":"10.1016/j.taap.2025.117426","DOIUrl":"10.1016/j.taap.2025.117426","url":null,"abstract":"<div><div>During the cardiac safety pharmacology decision-making process, a precise evaluation of the proarrhythmic liabilities of new drug candidates is essential to prevent serious side effects like torsade de pointes (TdP), which could result in sudden death. Based in part on <em>in silico</em> reconstruction of the human ventricular cardiomyocyte action potential (AP), the Comprehensive <em>in vitro</em> Proarrhthymia Assay (CiPA) initiative aims to achieve this goal. Because it is based on a significant amount of human data, the O'Hara-Rudy dynamic model is the first algorithm approved by the CiPA initiative for AP modeling. This algorithm was used to build a new database (<span><span>www.scaptest.com</span><svg><path></path></svg></span> for Safe Cardiac Action Potential test) in order to fully describe the <em>in silico</em> cardiac safety profile of a very large set of 200 compounds based on their concentration required to induce effects on AP shape and time course (resting membrane potential, AP maximal amplitude, AP duration) as well as on various predictive safety parameters extrapolated from this AP (triangulation, transmural dispersion of repolarization, reverse use dependence, likelihood of inducing early afterdepolarization (EAD), occurrence of EAD, threshold leading to EAD). This description of the <em>in silico</em> cardiac safety profile helps warn against the use of certain compounds possibly inducing cardiac safety issues (such as TdP or inexcitability) at least at high concentrations.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117426"},"PeriodicalIF":3.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254249","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":"BASP1/HTRA2 axis, targeted by miR-7a-5p, exerted a pro-apoptosis role in myocardial ischemia/reperfusion injury","authors":"Congna Zi ,&nbsp;Ying Zhu ,&nbsp;Xian Ma ,&nbsp;Yulei Wei","doi":"10.1016/j.taap.2025.117437","DOIUrl":"10.1016/j.taap.2025.117437","url":null,"abstract":"<div><div>Apoptosis is a main cause of myocardial injury in myocardial ischemia/reperfusion injury (MIRI). Brain abundant membrane attached signal protein 1 (BASP1) was an apoptosis regulator that may be involved in the myocardial apoptosis during MIRI. In this study, we established the MIRI mouse model by ligating the left anterior descending coronary artery of mice for 30 min followed by reperfusion for 24 h. BASP1 was upregulated in the MIRI model. The adenoviruses carrying shRNA that specifically targets BSAP1 were used to downregulate BASP1 expression in myocardium. BASP1 silencing alleviated myocardial infarction and improved cardiac function. Furthermore, BASP1 silencing inhibited MIRI-induced myocardial apoptosis as evidenced by decreased TUNEL-positive cells and reduced caspase-3 and caspase-9 activities. Meanwhile, cell model was also established by culturing mouse HL-1 cells in a hypoxic (H) environment for 8 h, followed by reoxygenation (R) for 12 h. H/R upregulated BASP1 expression and BASP1 knockdown reduced H/R-induced apoptosis. Besides, the mRNA-sequencing analysis was conducted to explore the underlying mechanism by which BASP1 functions. HtrA serine peptidase 2 (HTRA2), one of the 1975 differentially expressed genes (<em>p</em> &lt; 0.05, |log₂FC| &gt; 1.5), was identified as candidates of molecular targets of BASP1 through gene ontology annotation and enrichment analysis. Introduction of HTRA2 to HL-1 cells counteracted the impact of BASP1 knockdown. MiR-7a-5p was found to target the 3′-untranslated regions of BASP1 and inhibit its expression through dual luciferase reporter assay. Collectively, BASP1/HTRA2 axis, regulated by miR-7a-5p, may be the promoter of MIRI process, indicating that BASP1/HTRA2 axis is a potential target for treating MIRI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117437"},"PeriodicalIF":3.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249761","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":"Identifying risk factors for methotrexate-induced acute kidney injury despite full prevention in patients with primary central nervous system lymphoma","authors":"Wen-Ying Lin ,&nbsp;Chun-Kuang Tsai ,&nbsp;Chiu-Mei Yeh ,&nbsp;Chia-Jen Liu","doi":"10.1016/j.taap.2025.117436","DOIUrl":"10.1016/j.taap.2025.117436","url":null,"abstract":"<div><h3>Background</h3><div>Primary central nervous system lymphoma (PCNSL) accounts for 3 % of all brain tumors worldwide and high-dose methotrexate (HD-MTX) is used as the frontline chemotherapy. Given the renal excretion of methotrexate, we aimed to identify risk factors for HD-MTX–induced acute kidney injury (AKI) in patients with PCNSL. A comprehensive retrospective cohort study was conducted on newly diagnosed PCNSL patients who received HD-MTX chemotherapy.</div></div><div><h3>Methods</h3><div>Baseline characteristics, comorbidities, and laboratory data were collected at diagnosis and prior to each chemotherapy cycle. Serum methotrexate levels were measured at 24–48, 48–72, and 72–96 h post-infusion. Generalized estimating equations were used to identify risk factors for AKI. Among 146 patients with PCNSL, 108 received HD-MTX-based regimens, comprising 576 treatment cycles.</div></div><div><h3>Results</h3><div>Univariate analysis revealed that male gender, serum MTX levels ≥2 μmol/L at 48–72 h post-infusion, fluid accumulation in third spaces, low serum albumin, elevated blood urea nitrogen (BUN), and serum creatinine ≥2.0 mg/dL were all associated with increased AKI risk. In multivariate analysis, serum MTX levels ≥2 μmol/L and fluid accumulation in third spaces remained significant risk factors for AKI. Notably, none of the comorbidities were associated with the incidence of AKI.</div></div><div><h3>Conclusions</h3><div>These findings indicate that third-space fluid accumulation and elevated serum methotrexate levels at 48–72 h post-infusion are significant independent predictors of AKI in PCNSL patients receiving HD-MTX. We also developed a clinically applicable risk scoring system with strong predictive performance to support early identification and management of high-risk patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117436"},"PeriodicalIF":3.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249762","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}