Toxicology in Vitro最新文献

Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model. 使用三维人肝细胞球体模型评估大麻二酚诱导的有丙戊酸和无丙戊酸肝损伤。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-08-05 DOI: 10.1016/j.tiv.2025.106126

Jessica L Beers, Shalon L Harvey, Raeanne M Lanphier, Blake R Rushing, Susan L McRitchie, Susan J Sumner, Klarissa D Jackson

{"title":"Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model.","authors":"Jessica L Beers, Shalon L Harvey, Raeanne M Lanphier, Blake R Rushing, Susan L McRitchie, Susan J Sumner, Klarissa D Jackson","doi":"10.1016/j.tiv.2025.106126","DOIUrl":"10.1016/j.tiv.2025.106126","url":null,"abstract":"<p><p>Cannabidiol (CBD) and valproate (VPA) are anti-epileptic medications commonly co-prescribed to treat seizures due to Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children. Clinical trial data have demonstrated that CBD carries a risk for severe hepatotoxicity that is greatly increased when prescribed with VPA through an unknown mechanism. The aim of this study was to investigate CBD-induced liver injury in combination with VPA using an in vitro liver model. Three-dimensional human hepatocyte spheroids are an emerging in vitro system that allows investigation of long-term toxicity. Spheroids derived from primary human hepatocytes were treated with vehicle control, 2-200 μM CBD, 0.5-20 mM VPA, CBD + VPA, and 0.1-10 mM acetaminophen (positive control). After 24 h, 8 days, and 15 days of exposure, spheroids were analyzed for ATP depletion, urea production, and CBD and VPA metabolite generation. Untargeted metabolomic analysis was also conducted. A delayed-onset, dose-dependent hepatotoxicity was observed in spheroids exposed to each drug treatment compared to vehicle control. This study is the first to recapitulate the hepatotoxic drug interaction of CBD and VPA in vitro and demonstrates the utility of human hepatocyte spheroids for toxicity studies. Future work is needed to examine mechanisms of CBD-induced hepatotoxicity with VPA.</p>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":" ","pages":"106126"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic stability and effects of microsomal enzymes on the activity of the sonic hedgehog pathway inhibitor piperonyl butoxide 代谢稳定性和微粒体酶对超音hedgehog途径抑制剂胡椒酰丁醇活性的影响。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-10-07 DOI: 10.1016/j.tiv.2025.106156

Kenneth S. Rivera-González , Cameron O. Scarlett , Robert J. Lipinski

{"title":"Metabolic stability and effects of microsomal enzymes on the activity of the sonic hedgehog pathway inhibitor piperonyl butoxide","authors":"Kenneth S. Rivera-González , Cameron O. Scarlett , Robert J. Lipinski","doi":"10.1016/j.tiv.2025.106156","DOIUrl":"10.1016/j.tiv.2025.106156","url":null,"abstract":"<div><div>The pesticide synergist piperonyl butoxide (PBO) is a methylenedioxy compound used in many pesticide formulations. Previous studies identified PBO as an inhibitor of the Sonic hedgehog (Shh) signaling pathway and linked prenatal PBO exposure to adverse developmental outcomes. Mixed-function oxidases have been proposed to metabolize PBO, but the specific enzymes involved in its depletion have not been identified. Here we examined the metabolic stability of PBO in the presence of human liver microsomes and the involvement of the CYP-450 (CYPs) and FMO enzyme families on the <em>in vitro</em> depletion of PBO. We found that PBO is readily depleted by microsomal enzymes in the presence of NADPH. The CYP inhibitor SKF-525 A significantly decreased PBO depletion, while the FMO inhibitor methimazole did not. We then examined the depletion capacity of individual CYPs, focusing on isoforms with common human polymorphisms. CYP2C19, CYP2C9, and CYP3A4 exhibited the greatest PBO depletion capacity, while CYP1A2 and CYP2D6 demonstrated moderate capacity. Finally, the effect of microsomal activity on the antagonist activity of PBO against the Sonic hedgehog (Shh) pathway was assessed. Microsomal depletion reduced but did not eliminate the antagonistic activity of PBO on Shh pathway signaling activity. Collectively, these findings suggest a major role for mixed-function oxidases in PBO depletion and indicate the possible involvement of specific CYP isoforms.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"111 ","pages":"Article 106156"},"PeriodicalIF":2.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253779","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}

引用次数: 0

Liposomal nanoparticles containing adenosine triphosphate targeted by heart-specific peptide ligands as antidotes for aluminum phosphide poisoning in isolated rat cardiomyocyte cell line 心脏特异性肽配体靶向三磷酸腺苷纳米粒脂质体作为离体大鼠心肌细胞系磷化铝中毒的解毒剂。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-10-06 DOI: 10.1016/j.tiv.2025.106155

Roghayeh Jahani , Hamidreza Mohammadi , Mohammad Seyedabadi , Vajihe Alinezhad , Javad Akhtari

{"title":"Liposomal nanoparticles containing adenosine triphosphate targeted by heart-specific peptide ligands as antidotes for aluminum phosphide poisoning in isolated rat cardiomyocyte cell line","authors":"Roghayeh Jahani , Hamidreza Mohammadi , Mohammad Seyedabadi , Vajihe Alinezhad , Javad Akhtari","doi":"10.1016/j.tiv.2025.106155","DOIUrl":"10.1016/j.tiv.2025.106155","url":null,"abstract":"<div><div>Aluminum phosphide (ALP) poisoning remains a critical challenge because of the limited number of treatment options. ALP disrupts the electron transport chain, causing ATP depletion, oxidative stress, and cytotoxicity. This study developed ischemic myocardium-targeting peptide (IMTP)-conjugated ATP-loaded liposomes (ATP-L) to mitigate ALP-induced cardiotoxicity. ATP-L was prepared via thin-film hydration and freeze–thaw methods, followed by peptide conjugation via maleimide-PEG<sub>2000</sub>-DSPE. Liposome characterization revealed average sizes of 134.8 nm (DLS) and 113 nm (TEM), zeta potential of +11.33 mV, PDI of 0.17, and ATP encapsulation efficiency of 41 %.</div><div>In this study, the rat cardiomyocyte cell line (H<sub>9</sub>C<sub>2</sub>) was used. In H<sub>9</sub>C<sub>2</sub> cells, ALP exhibited dose-dependent toxicity, whereas ATP, non-targeted ATP-loaded liposomes (NT-ATP-L), and ATP-L showed no cytotoxicity. Co-treatment with ATP, NT-ATP-L, and ATP-L via ALP (18.27 μg/ml) for 3 h significantly reduced the levels of oxidative stress markers, restoring the cellular redox balance.</div><div>These findings highlight ATP-L as a promising antioxidant nanotherapy for treating ALP poisoning. ATP-L combats ALP-induced cardiotoxicity by restoring ATP and reducing oxidative damage. The use of IMTP ensures precise targeting to ischemic cardiac tissues, potentially improving efficacy and minimizing off-target effects. This strategy offers a novel approach to managing ALP toxicity. Further studies are needed to validate the in vivo results and optimize the formulation for clinical use. Overall, ATP-L represents a significant advancement in targeted nanomedicine for toxicological emergencies.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106155"},"PeriodicalIF":2.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253793","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}

引用次数: 0

Effects of heated tobacco products and conventional cigarettes on oxidative stress and inflammation in alveolar macrophages 加热烟草制品和传统香烟对肺泡巨噬细胞氧化应激和炎症的影响。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-26 DOI: 10.1016/j.tiv.2025.106151

Ok Joo Sul , Hye Won Choi , Seo Hee Park , Min Ju Kim , Seung Won Ra

{"title":"Effects of heated tobacco products and conventional cigarettes on oxidative stress and inflammation in alveolar macrophages","authors":"Ok Joo Sul , Hye Won Choi , Seo Hee Park , Min Ju Kim , Seung Won Ra","doi":"10.1016/j.tiv.2025.106151","DOIUrl":"10.1016/j.tiv.2025.106151","url":null,"abstract":"<div><div>Oxidative stress in macrophages is a major factor contributing to smoking-induced chronic respiratory diseases. However, the oxidative stress induced by heat-not-burn tobacco products (HTP) and conventional cigarettes (3R4F) in macrophages has not been sufficiently investigated. This study compared the effects of HTP and 3R4F cigarettes on cytotoxicity and oxidative stress. We also investigated the underlying mechanisms of autophagy-induced inflammation in macrophages. Our results showed that both HTP and 3R4F cigarette aerosols induced cytotoxicity; however, HTP aerosol was less cytotoxic than conventional cigarette aerosol in RAW264.7 cells. In addition, both aerosols resulted in increased reactive oxygen species (ROS) levels in RAW 264.7 and bone marrow-derived macrophages (BMMs), although the levels were lower for HTP aerosol than for 3R4F aerosol. Additionally, acute exposure to HTP aerosol elevated the levels of IL-1β, IL-6, and TNF-α in macrophages. Oxidative stress-triggered TFEB oxidation induced TFEB nuclear translocation, thereby enhancing autophagy and inflammation in HTP- and 3R4F-exposed macrophages. In conclusion, our study demonstrated that aerosols from HTP and 3R4F cigarettes increased the cytotoxicity in macrophages. Cigarette aerosols increase oxidative stress, which triggers TFEB oxidation and increases its nuclear translocation. TFEB oxidation leads to increased autophagy and inflammation in HTP- or 3R4F aerosol-exposed macrophages. Exposure to HTP aerosols resulted in lower cytotoxicity, oxidative stress, and inflammatory responses than the exposure to conventional cigarettes in vitro.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106151"},"PeriodicalIF":2.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187579","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}

引用次数: 0

Tributyltin propionate and tributyltin salicylate represent novel RXR ligands: Effects on transcriptional activity of thyroid hormone receptor and vitamin D3 receptor 丙酸三丁基锡和水杨酸三丁基锡为新型RXR配体：对甲状腺激素受体和维生素D3受体转录活性的影响

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-25 DOI: 10.1016/j.tiv.2025.106153

Dana Macejova , Jakub Kollar , Zdenek Dvorak , Daniela Schuster , Julius Brtko

{"title":"Tributyltin propionate and tributyltin salicylate represent novel RXR ligands: Effects on transcriptional activity of thyroid hormone receptor and vitamin D3 receptor","authors":"Dana Macejova , Jakub Kollar , Zdenek Dvorak , Daniela Schuster , Julius Brtko","doi":"10.1016/j.tiv.2025.106153","DOIUrl":"10.1016/j.tiv.2025.106153","url":null,"abstract":"<div><div>Several organometallic trialkyltins or triaryltins are known to act as retinoid X receptor (RXR) agonists, which were also reported to exert eminent cytotoxic properties. In the present study, binding properties of tributyltin propionate (TBT-P) and tributyltin salicylate (TBT-S) in RXRα molecule were theoretically investigated using docking in Schrödinger small molecule drug discovery suite. Our data has shown that TBT-P and TBT-S bind in the binding pocket of RXRα and represent novel RXR agonists. <em>In vitro</em> data has shown that both TBT-P and TBT-S exert transcriptional activity under basal and ligand-activated conditions through RXR − nuclear thyroid hormone receptor (TR) heterodimer in the human reporter cell line for the assessment of thyroid receptor transcriptional activity (PZ-TR). In the human reporter cell line, enabling sensitive and selective identification of nuclear dihydroxyvitamin D<sub>3</sub> receptor (VDR) agonists (IZ-VDRE), TBT-P and TBT-S did not exert any transcriptional activity through VDR under basal and ligand-activated conditions, which is in agreement with the properties of the non-permissive type of RXR-VDR heterodimer. Our <em>in silico</em> and <em>in vitro</em> data demonstrate that both organometallic compounds TBT-P and TBT-S represent new nuclear retinoid X receptor agonists.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106153"},"PeriodicalIF":2.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158180","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}

引用次数: 0

The pesticide fungicide difenoconazole modulates the biophysical properties of sodium channel Nav1.5 农药杀菌剂异苯唑调节钠通道Nav1.5的生物物理性质。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-24 DOI: 10.1016/j.tiv.2025.106152

V. Fogaça-Santos , F.S. Alcântara , M.R.L. Conceição , L.P. Marques , J.L. Teixeira-Fonseca , D.J.B. Orts , J. Branquinho , R.L. Morais , K.O. Mota , D.S. Souza , J.B. Pesquero , D. Roman-Campos

{"title":"The pesticide fungicide difenoconazole modulates the biophysical properties of sodium channel Nav1.5","authors":"V. Fogaça-Santos , F.S. Alcântara , M.R.L. Conceição , L.P. Marques , J.L. Teixeira-Fonseca , D.J.B. Orts , J. Branquinho , R.L. Morais , K.O. Mota , D.S. Souza , J.B. Pesquero , D. Roman-Campos","doi":"10.1016/j.tiv.2025.106152","DOIUrl":"10.1016/j.tiv.2025.106152","url":null,"abstract":"<div><div>Difenoconazole (DIF) is a widely used fungicide in agriculture, but it is unknown if it can modulate the excitability of the heart tissue. Thus, we investigated the acute effect of DIF on the electrical properties of heart tissue, with a particular focus on the cardiac sodium channel (Na<sub>v</sub>1.5) using transient expression of human Na<sub>v</sub>1.5 in human kidney cell (HEK) and human cardiomyocytes derived from induced pluripotent stem cells (CM-hiPSCs). DIF reduced the peak amplitude of sodium current (I<sub>Na</sub>) in a concentration dependent manner. While DIF did not alter the voltage dependence of activation, it shifted the I<sub>Na</sub> inactivation curve to more negative potentials and delayed the recovery from inactivation. <em>In silico</em> simulation identified aminoacids Thr1710 and Val1765 as critical for the interaction between DIF with Na<sub>v</sub>1.5. DIF partially blocked the late sodium current induced by deltamethrin, a pyrethroid pesticide, suggesting a potential interaction between these compounds in the environment. In CM-hiPSCs, DIF completely abolished the action potential. These findings suggest that DIF may modulate the biophysical properties of Na<sub>v</sub>1.5 and modulate cellular excitability which may cause reduced heart excitability, an DIF can also counteracting the effects of pyrethroid pesticides, but further studies using DIF concentrations closer to human exposure levels are necessary.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106152"},"PeriodicalIF":2.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180280","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}

引用次数: 0

First toxicity profile of aminoindane-based new psychoactive substances: 2-aminoindane (2-AI, CAS: 2975-41-9) and N-Methyl-2-aminoindane (NM-2-AI, CAS: 24445–44–1) – comprehensive prediction of toxicological endpoints important from clinical and forensic perspective using in silico multi- approach 基于氨基吲哚胺的新型精神活性物质：2-氨基吲哚胺（2-AI, CAS: 2975-41-9）和n -甲基-2-氨基吲哚胺（NM-2-AI, CAS: 24445-44-1）的第一个毒性谱-从临床和法医角度使用硅多方法综合预测毒理学终点很重要。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-24 DOI: 10.1016/j.tiv.2025.106149

Kamil Jurowski , Adrian Frydrych

{"title":"First toxicity profile of aminoindane-based new psychoactive substances: 2-aminoindane (2-AI, CAS: 2975-41-9) and N-Methyl-2-aminoindane (NM-2-AI, CAS: 24445–44–1) – comprehensive prediction of toxicological endpoints important from clinical and forensic perspective using in silico multi- approach","authors":"Kamil Jurowski , Adrian Frydrych","doi":"10.1016/j.tiv.2025.106149","DOIUrl":"10.1016/j.tiv.2025.106149","url":null,"abstract":"<div><div>This study provides the first toxicity profile of two aminoindane-based new psychoactive substances (NPS): 2-aminoindane (2-AI) and <em>N</em>-methyl-2-aminoindane (NM-2-AI), using a multi-method <em>in silico</em> approach. Tools including Percepta, ProTox 3.0, ADMETlab 3.0, VEGA QSAR, TEST, QSAR Toolbox, and STopTox were applied to evaluate acute toxicity, systemic organ effects, genotoxicity, skin and eye irritation, and cardiotoxicity. Both compounds were predicted to be acutely toxic <em>via</em> oral, dermal, and inhalation routes. Quantitative LD₅₀ values (rat, oral) ranged from 150 to 560 mg/kg (Percepta), 259.7–112.6 mg/kg (VEGA), and 326–360 mg/kg (ProTox 3.0). Health effect predictions indicated high probabilities of cardiovascular toxicity (2-AI: 80 %, NM-2-AI: 82 %) and pulmonary involvement (66 % and 65 %, respectively). NM-2-AI showed a higher likelihood of genotoxicity (Ames test) with a probability of 66.3 % (ADMETlab), compared to 2-AI (58.7 %). Both substances were predicted to be non-irritant to the eye, but skin irritation was probable for 2-AI (80 %, StopTox) and less so for NM-2-AI (60 %). hERG inhibition risk was low (IC₅₀: 391.7 μM for 2-AI; 126.9 μM for NM-2-AI). The <em>in silico</em> multi-tool strategy yielded convergent and interpretable data, supporting early toxicological characterization. These results are relevant for clinical management of NPS intoxications and for forensic interpretation in the absence of experimental data.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106149"},"PeriodicalIF":2.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180335","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}

引用次数: 0

Collaborative evaluation of in silico predictions for high throughput toxicokinetics 高通量毒物动力学的协同评估。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-20 DOI: 10.1016/j.tiv.2025.106150

John F. Wambaugh , Nisha S. Sipes , Gilberto Padilla Mercado , Jon A. Arnot , Linda Bertato , Trevor N. Brown , Nicola Chirico , Christopher Cook , Daniel E. Dawson , Sarah E. Davidson-Fritz , Stephen S. Ferguson , Michael-Rock Goldsmith , Chris M. Grulke , Richard S. Judson , Kamel Mansouri , Grace Patlewicz , Ester Papa , Prachi Pradeep , Alessandro Sangion , Risa R. Sayre , Michael J. Devito

{"title":"Collaborative evaluation of in silico predictions for high throughput toxicokinetics","authors":"John F. Wambaugh , Nisha S. Sipes , Gilberto Padilla Mercado , Jon A. Arnot , Linda Bertato , Trevor N. Brown , Nicola Chirico , Christopher Cook , Daniel E. Dawson , Sarah E. Davidson-Fritz , Stephen S. Ferguson , Michael-Rock Goldsmith , Chris M. Grulke , Richard S. Judson , Kamel Mansouri , Grace Patlewicz , Ester Papa , Prachi Pradeep , Alessandro Sangion , Risa R. Sayre , Michael J. Devito","doi":"10.1016/j.tiv.2025.106150","DOIUrl":"10.1016/j.tiv.2025.106150","url":null,"abstract":"<div><div>High throughput toxicokinetic (HTTK) methods address chemical risk assessment data gaps but require chemical-specific values that can be obtained by <em>in vitro</em> measurements or <em>in silico</em> models. In this study, seven quantitative structure property relationship (QSPR) models were used to estimate intrinsic hepatic clearance (Cl<sub>int</sub>), fraction of chemical unbound in plasma (f<sub>up</sub>), and/or TK elimination half-life (t<sub>½</sub>). Performance of the QSPR models was evaluated using literature time-course <em>in vivo</em> TK data, mainly from rats. Simulations of the <em>in vivo</em> data were made with a high throughput physiologically based TK (HT-PBTK) model using the different QSPR model predictions as inputs. We estimate that using rat <em>in vivo</em> data to evaluate QSPR models trained on human <em>in vitro</em> measured data might inflate error estimates by as much as root mean squared log<sub>10</sub> error (RMSLE) 0.8. A sensitivity analysis showed that Cl<sub>int</sub> and f<sub>up</sub> parameters inform predictions of area under the curve (AUC) and steady-state concentration (C<sub>ss</sub>). We estimate that AUC can be predicted by HTTK with RMSLE 0.9 using <em>in vitro</em> measurements and 0.6–0.8 using QSPR model values. We anticipate that, for some novel compounds, QSPRs for HTTK input parameters will give predictions of TK similar to those based on <em>in vitro</em> measurements.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106150"},"PeriodicalIF":2.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126470","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}

引用次数: 0

Synergistic and divergent effects of dietary sugars on hepatocyte viability and steatosis 膳食糖对肝细胞活力和脂肪变性的协同和发散效应。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-18 DOI: 10.1016/j.tiv.2025.106148

Ajay Kumar , Garhima Arora , Deepika Kumari , Harish Changotra , Samrat Chatterjee

{"title":"Synergistic and divergent effects of dietary sugars on hepatocyte viability and steatosis","authors":"Ajay Kumar , Garhima Arora , Deepika Kumari , Harish Changotra , Samrat Chatterjee","doi":"10.1016/j.tiv.2025.106148","DOIUrl":"10.1016/j.tiv.2025.106148","url":null,"abstract":"<div><div>Our study explores the effects of glucose, fructose, and sucrose on hepatocyte health, focusing on cell viability and lipid accumulation. Hepatocyte cells (HepG2) were exposed to a range of concentrations of glucose, fructose and sucrose, both individually and in combination, over 24, 48, and 72 h. Cell viability was monitored using the MTT assay, while lipid accumulation was estimated fluorometrically using Nile red staining. Our findings suggest that higher concentrations of fructose significantly improves cell viability in a dose-dependent manner, especially in hepatocyte cells exposed to fructose for extended duration. Additionally, a time-dependent increase in lipid accumulation was seen, particularly in cells exposed to fructose. Interestingly, enhanced hepatocyte viability was noted with combinations of glucose with fructose or sucrose, without detrimental effects. Lipid accumulation was more pronounced with glucose-fructose combinations. These results provide insights into the differential effects of dietary sugars on liver health and metabolism, with implications for understanding metabolic disorders like MASLD and MASH.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106148"},"PeriodicalIF":2.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103243","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}

引用次数: 0

Binding of plutonium and americium to small molecular weight ligands favors their paracellular transfer across lung epithelium in vitro 钚和镅与小分子量配体的结合有利于其在体外肺上皮细胞旁转移。

IF 2.7 3区医学

Toxicology in Vitro Pub Date : 2025-09-18 DOI: 10.1016/j.tiv.2025.106146

G. Drouet , A. Bourgois , K. Devilliers , M. Defrance , A. Van der Meeren

{"title":"Binding of plutonium and americium to small molecular weight ligands favors their paracellular transfer across lung epithelium in vitro","authors":"G. Drouet , A. Bourgois , K. Devilliers , M. Defrance , A. Van der Meeren","doi":"10.1016/j.tiv.2025.106146","DOIUrl":"10.1016/j.tiv.2025.106146","url":null,"abstract":"<div><div>Pulmonary absorption is a critical step in the time-dependent processes governing actinide biodistribution and toxicity following internal contamination by inhalation. The current study was undertaken to investigate on a simple in vitro Calu-3 model the mechanisms involved in the transfer across epithelial cells of plutonium (Pu) and americium (Am) as a function of their intrinsic properties (nature, physicochemical form) or their association with serum proteins, inorganic ligands or synthetic chelating agents. Both the contribution of the transcellular and paracellular routes to the transfer of these various forms were studied. Results show that uptake of Pu and Am by epithelial cells is not positively correlated with their transfer, which suggests that radionuclides transcytosis is a continuous process in comparison with the quick translocation of Pu/Am-small size complexes. Furthermore, reducing epithelial cells paracellular permeability with the glucocorticoid hormone Dexamethasone (DEX) resulted into a lower transfer of Pu citrate, and of both actinides in the presence of diethylene triamine pentaacetic acid (DTPA) and 3,4,3-LI(1,2-HOPO). Taken together, these results seem to indicate that a paracellular pathway may be responsible, at least partly, for the higher pulmonary absorption observed in vivo for actinides bound to low-molecular weight ligands such as citrate, DTPA or HOPO.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"110 ","pages":"Article 106146"},"PeriodicalIF":2.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103256","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}

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