Toxicology in Vitro最新文献

A group of novel polyfluoroether substances affects lipid metabolism in human hepatocyte HepaRG cells less than classic perfluoroalkyl compounds.

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-12 DOI: 10.1016/j.tiv.2025.106024

Faezeh Sadrabadi, Wiebke Alker, Heike Sprenger, Albert Braeuning, Thorsten Buhrke

Per- and polyfluoroalkyl substances (PFAS) are used for numerous industrial applications including the production of fluorosurfactants. Some prominent PFAS, e.g., perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), are non-degradable and therefore persist in the environment. They display various toxic properties including dysregulation of hepatic lipid metabolism. At the molecular level, these effects are mainly based on a PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPARα). A group of novel, degradable polyfluoroether compounds has been designed as building blocks for the production of alternative, degradable fluorosurfactants. In the present study, we examined the capacity of four of these novel polyfluoroether compounds to induce PPARα activation, increase intracellular triglyceride accumulation, and produce a cytotoxic response. In contrast to some classic PFAS including PFOA and PFOS, the novel compounds neither activated PPARα in a transactivation assay, nor did they induce expression of selected PPARα-dependent target genes in differentiated HepaRG cells, a model for human hepatocytes. They also did not induce triglyceride accumulation in HepaRG cells. The in vitro data indicate that the polyfluoroether compounds tested in the present study are not PPARα agonists. Since PPARα agonist activity is often associated with toxic responses, it can be assumed that these substances are less toxic than classic PFAS such as PFOA and PFOS, at least with respect to PPARα-dependent toxicity mechanisms.

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引用次数: 0

Assessing the safety of midazolam: A comprehensive analysis of adverse events from FAERS

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-11 DOI: 10.1016/j.tiv.2025.106023

Jieyuan Chen , Zhaojun Wang , Li Wei , Songsong Mao

Midazolam, a potent sedative from the benzodiazepine class, is widely used in anesthesia and intensive care, but it has been linked to severe and life-threatening cardiopulmonary adverse events (AEs). This study investigated real-world AEs associated with midazolam using data from the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS) from 2004 to 2024. Disproportionality analysis was performed using four signal detection methods—reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker—to assess midazolam-related AEs. A total of 2952 AE reports were identified, involving seven system organ classes, with 31 specific AEs meeting criteria across all four algorithms. Unexpected AEs not listed in the product label, such as seizure, coma, respiratory failure, anaphylactic shock, and hypothermia, were also observed, with most AEs occurring within the first 10 days of midazolam use. This pharmacovigilance study highlights the need for increased awareness of serious and unexpected AEs, including respiratory failure, anaphylactic shock, hypothermia, and metabolic acidosis, to promote safer use of midazolam in clinical practice.

咪达唑仑是苯二氮卓类药物中的一种强效镇静剂，被广泛用于麻醉和重症监护，但它与严重和危及生命的心肺不良事件（AEs）有关。本研究利用美国食品和药物管理局（FDA）不良事件报告系统（FAERS）2004年至2024年的数据，调查了现实世界中与咪达唑仑相关的不良事件。使用四种信号检测方法--报告几率比、报告比例比、贝叶斯置信度传播神经网络和多项目伽马泊松收缩器进行了比例失调分析，以评估与咪达唑仑相关的AE。共发现 2952 例 AE 报告，涉及七个系统器官类别，其中 31 例特定 AE 符合所有四种算法的标准。还观察到了产品标签中未列出的意外AE，如癫痫发作、昏迷、呼吸衰竭、过敏性休克和体温过低，大多数AE发生在使用咪达唑仑的头10天内。这项药物警戒研究强调，有必要提高对呼吸衰竭、过敏性休克、低体温和代谢性酸中毒等严重和意外AE的认识，以促进在临床实践中更安全地使用咪达唑仑。

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引用次数: 0

β-sitosterol protects against ANIT-induced hepatotoxicity and cholestasis via FXR activation

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-11 DOI: 10.1016/j.tiv.2025.106020

Yuhui Yan , Wenyu Wang , Aiwen Yan , Haonan Zhu , Qiang Meng

Cholestasis, a condition marked by bile acid accumulation in the liver and body systems, leads to liver dysfunction and cirrhosis. Currently, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for Cholestasis. Thus, new therapeutic approaches need to be developed. In this study, we validated the liver-protective properties of β-sitosterol (SIT), a key bioactive element abundant in plants, against hepatic toxicity and cholestasis induced by alpha-naphthylisothiocyanate(ANIT), while elucidating its mechanisms of action both in vivo and in vitro. SIT's FXR activation was confirmed via molecular docking and dual-luciferase assays. In the mechanisms of SIT hepatoprotection, the expression levels of bile salt export pump (Bsep) and multidrug resistance protein2 (Mrp2) which are bile acid efflux transporter, and sulfate transferase 2a1 (Sult2a1) which is a bile acid metabolizing enzyme were all increased by SIT, whereas the expression of uptake transporter sodium taurocholate transporting polypeptide (Ntcp), bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) was decreased by SIT. In addition, SIT alleviated liver inflammation by suppressing inflammatory factor expression. However, FXR antagonist guggulsterone and FXR siRNA abolished SIT's improvements in liver histology, bile acid transporters, and enzymes. Conclusively, through activating FXR, SIT provides a protective effect against hepatotoxicity and cholestasis. SIT might serve as a new potential therapeutic strategy for the treatment of cholestatic liver diseases.

胆汁淤积症是一种以胆汁酸在肝脏和身体系统中积聚为特征的疾病，会导致肝功能障碍和肝硬化。目前，熊去氧胆酸（UDCA）和奥贝胆酸（OCA）是美国食品及药物管理局批准的仅有的两种治疗胆汁淤积症的药物。因此，需要开发新的治疗方法。在这项研究中，我们验证了β-谷甾醇（SIT）的保肝特性，它是植物中丰富的一种关键生物活性元素，可对抗α-萘基异硫氰酸酯（ANIT）诱导的肝毒性和胆汁淤积，同时阐明了其体内和体外的作用机制。通过分子对接和双荧光素酶试验证实了 SIT 对 FXR 的激活作用。在 SIT 的保肝机制中，胆汁酸流出转运体胆盐输出泵（Bsep）和多药耐药蛋白 2（Mrp2）以及胆汁酸代谢酶硫酸转移酶 2a1 （Sult2a1）的表达水平均因 SIT 而升高、而吸收转运体牛磺胆酸钠转运多肽（Ntcp）、胆汁酸合成酶胆固醇 7α- 羟化酶（Cyp7a1）和氧杂环醇 12α- 羟化酶（Cyp8b1）的表达则因 SIT 而降低。此外，SIT 还能通过抑制炎症因子的表达来缓解肝脏炎症。然而，FXR拮抗剂古格列酮和FXR siRNA会抑制SIT对肝组织学、胆汁酸转运体和酶的改善作用。总之，通过激活 FXR，SIT 对肝毒性和胆汁淤积具有保护作用。SIT可能成为治疗胆汁淤积性肝病的一种新的潜在治疗策略。

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引用次数: 0

Using cimetidine to mitigate cisplatin-induced ototoxicity

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-11 DOI: 10.1016/j.tiv.2025.106025

Rahul Sinha , Si Ja Liu , Rebekah Lee , Julia Boyd , Kyla Geary , Dianzheng Zhang

Given the well-established role of organic cation transporter 2 (OCT2) in cisplatin uptake to the inner ear cells, and the fact that cimetidine is an FDA-approved drug with well-established inhibitory activity against OCT2, we hypothesized that inhibiting OCT2-mediated cisplatin uptake with cimetidine could eliminate or alleviate cisplatin-mediated ototoxicity. Our preliminary data showed that cisplatin can reduce the viability of House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in a dose-dependent manner, and cimetidine can effectively counteract this cisplatin-induced toxicity without affecting cisplatin's effect on cancer cells. Therefore, combined application of these drugs could ameliorate cisplatin ototoxicity with minimal impact on their anti-cancer effect.

引用次数: 0

Repression of bile salt efflux pump expression by tri-ortho-cresyl phosphate in cultured human hepatic cells

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-08 DOI: 10.1016/j.tiv.2025.106021

Valentin Tastet , Marc Le Vée , Jennifer Carteret , David Malnoë , Arnaud Bruyère , Olivier Fardel

Tri-ortho-cresyl phosphate (TOCP) is an environmental toxic pollutant, belonging to the chemical class of organophosphorus flame retardants and repressing hepatic membrane drug transporter expression. The present study investigated whether the liver canalicular bile salt efflux pump (BSEP) may also be targeted by TOCP. TOCP used at a non-cytotoxic concentration of 10 μM for 48 h was demonstrated to decrease BSEP mRNA expression in cultured hepatic HepaRG cells (by a 4.4-fold factor) and primary human hepatocytes (by a 2.5-fold factor). This effect was concentration-dependent (IC₅₀ = 0.8 μM) and was associated with a significant reduction of canalicular taurocholate secretion in HepaRG cells. It was not impaired by TOCP metabolism inhibitors. TOCP also potently antagonized farnesoid-X-receptor (FXR) mediated-BSEP up-regulation. The specific FXR antagonist DY268 decreased constitutive BSEP expression in HepaRG cells, as TOCP, suggesting a major implication of FXR antagonism in TOCP effects towards BSEP. The TOCP-mediated BSEP repression was finally predicted to potentially occur in vivo in response to a neurotoxic dose or to acute or chronic safe doses of TOCP. Taken together, these data demonstrate that the major bile salt transporter BSEP is a target for TOCP, which may support deleterious hepatotoxic effects of this chemical.

磷酸三正甲酚（TOCP）是一种环境有毒污染物，属于有机磷类阻燃剂，可抑制肝膜药物转运体的表达。本研究探讨了肝管胆盐外排泵（BSEP）是否也可能成为 TOCP 的靶标。实验证明，在无毒性浓度为 10 μM 的条件下使用 TOCP 48 小时后，培养的肝脏 HepaRG 细胞和原代人类肝细胞中的 BSEP mRNA 表达均会降低（降幅为 4.4 倍），原代人类肝细胞中的 BSEP mRNA 表达也会降低（降幅为 2.5 倍）。这种效应与浓度有关（IC50 = 0.8 μM），并与 HepaRG 细胞中管状陶氏胆酸盐分泌的显著减少有关。TOCP 代谢抑制剂不会对其产生影响。TOCP 还能有效拮抗类雌激素-X 受体（FXR）介导的-BSEP 上调。与 TOCP 一样，特异性 FXR 拮抗剂 DY268 也能降低 HepaRG 细胞中 BSEP 的组成型表达，这表明 FXR 拮抗作用在 TOCP 对 BSEP 的影响中起着重要作用。最后预测，TOCP 介导的 BSEP 抑制可能会在体内对神经毒性剂量或急性或慢性安全剂量的 TOCP 作出反应。综上所述，这些数据表明主要胆盐转运体 BSEP 是 TOCP 的靶标，这可能会支持这种化学物质的有害肝毒性效应。

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引用次数: 0

Anti-androgenetic effect of diphlorethohydroxycarmalol on testosterone-induced hair loss by inhibiting 5α-reductase and promoting Wnt/β-catenin signaling pathway in human dermal papilla cells

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-07 DOI: 10.1016/j.tiv.2025.106017

Seung Tae Im , Haeun Mun , Nalae Kang , Soo-Jin Heo , Seung-Hong Lee

Diphlorethohydroxycarmalol (DPHC), a marine phlorotannin compound derived from the brown alga Ishige okamurae, has been known to have a variety of biological effects. Recently, marine resources have been highlighted by their effects on ameliorating alopecia and related hair loss. Therefore, this study aimed to investigate the potential of DPHC isolated from I. okamurae as a hair loss treatment through examination of its anti-androgenic alopecia effects. Molecular docking analysis predicted that DPHC can be used as a 5α-reductase inhibitor superior to finasteride, which has traditionally been used as an anti-androgenic alopecia agent. In addition, DPHC significantly inhibited 5α-reductase activity in dihydrotestosterone (DHT)-treated human dermal papilla (HDP) cells, and downregulated hair growth inhibitor proteins such as AR, DKK1, TGF-β1, and IL-6. Moreover, DPHC treatment remarkably upregulated both the phosphorylation levels of GSK3β and expression levels of β-catenin in DHT-treated HDP cells, confirming the effects of DPHC on activating the Wnt/β-catenin signaling pathway. Therefore, these findings suggest that DPHC has a significant potential to prevent androgenic alopecia by promoting hair growth and preventing hair loss.

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引用次数: 0

In vitro human skin absorption of ethyl salicylate, pentyl salicylate, and (Z)-3-hexenyl salicylate from topical formulations: Effects on permeation and distribution

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-06 DOI: 10.1016/j.tiv.2025.106019

Kaushal Joshi , Darren M. Green , A. Christian Jones , Sophie E. Davies , Sophie G. Stocks , Arianna P. Bartlett , Anne Marie Api

In vitro human skin permeation and distribution of the fragrance materials ethyl salicylate (CAS 118–61-6, ES), (Z)-3-hexenyl salicylate (CAS 65405–77-8, HS) and pentyl salicylate (CAS 2050-08-0, PS) from separate 0.5 % (w/w) cream formulations were determined under unoccluded and occluded conditions for 24 h. For PS only, a 0.5 % (w/v) solution in 70/30 (v/v) ethanol/water was also assessed. Consumer relevant finite formulation doses were applied (5 mg/cm² or 5 μl/cm²) with salicylate application of ∼25 μg/cm². Although specifically assessing metabolism was not an aim, the common hydrolysis product salicylic acid (SA) was also quantified and included in overall test compound absorption values.

For ES, absorbed doses (mean ± standard error, SE) were 12.0 ± 1.0 and 24.7 ± 1.3 % applied dose under unoccluded and occluded conditions, respectively. For HS these values were 7.28 ± 0.52 and 11.1 ± 0.7 % applied dose. For the PS cream, corresponding values were 4.43 ± 0.48 and 7.52 ± 0.63 % applied dose. Whilst for the PS solution values were 8.26 ± 0.31 and 16.1 ± 0.7 % applied dose. The salicylate structure, application vehicle and level of occlusion impacted on the observed skin absorption. Considering salicylates are commonly used fragrance ingredients and have limited skin absorption data, the current research will be helpful in risk assessment to determine systemic exposure that is realistic and fill data gaps.

{"title":"In vitro human skin absorption of ethyl salicylate, pentyl salicylate, and (Z)-3-hexenyl salicylate from topical formulations: Effects on permeation and distribution","authors":"Kaushal Joshi , Darren M. Green , A. Christian Jones , Sophie E. Davies , Sophie G. Stocks , Arianna P. Bartlett , Anne Marie Api","doi":"10.1016/j.tiv.2025.106019","DOIUrl":"10.1016/j.tiv.2025.106019","url":null,"abstract":"<div><div>In vitro human skin permeation and distribution of the fragrance materials ethyl salicylate (CAS 118–61-6, ES), (Z)-3-hexenyl salicylate (CAS 65405–77-8, HS) and pentyl salicylate (CAS 2050-08-0, PS) from separate 0.5 % (<em>w</em>/w) cream formulations were determined under unoccluded and occluded conditions for 24 h. For PS only, a 0.5 % (<em>w</em>/<em>v</em>) solution in 70/30 (<em>v</em>/v) ethanol/water was also assessed. Consumer relevant finite formulation doses were applied (5 mg/cm<sup>2</sup> or 5 μl/cm<sup>2</sup>) with salicylate application of ∼25 μg/cm<sup>2</sup>. Although specifically assessing metabolism was not an aim, the common hydrolysis product salicylic acid (SA) was also quantified and included in overall test compound absorption values.</div><div>For ES, absorbed doses (mean ± standard error, SE) were 12.0 ± 1.0 and 24.7 ± 1.3 % applied dose under unoccluded and occluded conditions, respectively. For HS these values were 7.28 ± 0.52 and 11.1 ± 0.7 % applied dose. For the PS cream, corresponding values were 4.43 ± 0.48 and 7.52 ± 0.63 % applied dose. Whilst for the PS solution values were 8.26 ± 0.31 and 16.1 ± 0.7 % applied dose. The salicylate structure, application vehicle and level of occlusion impacted on the observed skin absorption. Considering salicylates are commonly used fragrance ingredients and have limited skin absorption data, the current research will be helpful in risk assessment to determine systemic exposure that is realistic and fill data gaps.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"104 ","pages":"Article 106019"},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375001","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

Predictive classification-based read-across for diverse functional vitiligo-linked chemical exposomes (ViCE): A new approach for the assessment of chemical safety for the vitiligo disease in humans

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-06 DOI: 10.1016/j.tiv.2025.106018

Shilpayan Ghosh, Sapna Kumari Pandey, Kunal Roy

We have explored a new approach using a similarity measure-based read-across derived hypothesis to address the precise risk assessment of vitiligo active chemicals. In this analysis, we initially prepared a data set by combining vitiligo active compounds taken from the previous literature with non-vitiligo chemicals, which are non-skin sensitizers reported in another literature. Afterward, we performed the manual curation process to obtain a curated dataset. Furthermore, the optimum similarity measure was identified from a validation set using a pool of 47 descriptors from the analysis of the most discriminating features. The identified optimum similarity measure (i.e., Euclidean distance-based similarity along with seven close source compounds) has been utilized in the read-across derived similarity-based classification studies on close source congeners concerning target compounds. In this study, we identified the positive and negative contributing features toward the assessment of vitiligo potential as well, including the estimation of target chemicals with better accuracy. The applicability domain status of the reported compounds was also studied, and the outliers were identified. As there are no comparative studies in this regard to the best of our knowledge, we can further affirm that it is the first report on the in-silico identification of potential vitiligo-linked chemical exposomes (ViCE) based on the similarity measure of the read-across.

{"title":"Predictive classification-based read-across for diverse functional vitiligo-linked chemical exposomes (ViCE): A new approach for the assessment of chemical safety for the vitiligo disease in humans","authors":"Shilpayan Ghosh, Sapna Kumari Pandey, Kunal Roy","doi":"10.1016/j.tiv.2025.106018","DOIUrl":"10.1016/j.tiv.2025.106018","url":null,"abstract":"<div><div>We have explored a new approach using a similarity measure-based read-across derived hypothesis to address the precise risk assessment of vitiligo active chemicals. In this analysis, we initially prepared a data set by combining vitiligo active compounds taken from the previous literature with non-vitiligo chemicals, which are non-skin sensitizers reported in another literature. Afterward, we performed the manual curation process to obtain a curated dataset. Furthermore, the optimum similarity measure was identified from a validation set using a pool of 47 descriptors from the analysis of the most discriminating features. The identified optimum similarity measure (i.e., Euclidean distance-based similarity along with seven close source compounds) has been utilized in the read-across derived similarity-based classification studies on close source congeners concerning target compounds. In this study, we identified the positive and negative contributing features toward the assessment of vitiligo potential as well, including the estimation of target chemicals with better accuracy. The applicability domain status of the reported compounds was also studied, and the outliers were identified. As there are no comparative studies in this regard to the best of our knowledge, we can further affirm that it is the first report on the in-silico identification of potential vitiligo-linked chemical exposomes (ViCE) based on the similarity measure of the read-across.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"104 ","pages":"Article 106018"},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374010","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

Marked differences in thyroxine (T4) metabolism following in vitro exposure of Wistar rat and human hepatocytes to several reference CAR/PXR nuclear receptor activators

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-03 DOI: 10.1016/j.tiv.2025.106016

Audrey Baze , Betty Ory , Liliia Horbal , Helen Tinwell , Lysiane Richert

Our study builds upon previous findings (Baze et al., 2024) by investigating species differences in thyroxine (T4) metabolism regulation by CAR/PXR activators using cryopreserved primary Wistar rat hepatocytes (PRH) and human hepatocytes (PHH) in 2D-sandwich over a 7-day treatment period. Daily exposure of PRH to phenobarbital, 5-Pregnen-3β-ol-20-one-16α‑carbonitrile (PCN) or dexamethasone increased T4 clearance over the last 24 h exposure (up to 60 %, 79 % and 67 % over control, respectively) and secretion of T4-glucuronide (T4-G; up to 463, 661 and 545 pmol/10⁶ cells over control, respectively). Effects were concentration-dependent for phenobarbital and PCN and highest at the lowest concentration for dexamethasone, while rifampicin barely affected T4 clearance and T4-G secretion. None of the compounds, at any tested concentration, affected these parameters in PHH. Additionally, mRNA expression data were consistent with the species-specific and concentration-dependent regulation of phase I Cyp/CYP, phase II Ugt/UGT and phase III Mrp2/MRP2 pathways occurring in rat and human liver following CAR/PXR activation. T4-UGT relative activity increased in PRH only, specifically by PCN, dexamethasone and phenobarbital. The comparison of PRH and PHH responses to compounds represents an important step towards using in vitro methods to reduce animal testing. We recommend using relative T4-UGT activity thresholds observed in PRH as benchmarks for defining compound-related effects across species, helping determine the human relevance of thyroid effects in rodents.

{"title":"Marked differences in thyroxine (T4) metabolism following in vitro exposure of Wistar rat and human hepatocytes to several reference CAR/PXR nuclear receptor activators","authors":"Audrey Baze , Betty Ory , Liliia Horbal , Helen Tinwell , Lysiane Richert","doi":"10.1016/j.tiv.2025.106016","DOIUrl":"10.1016/j.tiv.2025.106016","url":null,"abstract":"<div><div>Our study builds upon previous findings (<span><span>Baze et al., 2024</span></span>) by investigating species differences in thyroxine (T4) metabolism regulation by CAR/PXR activators using cryopreserved primary Wistar rat hepatocytes (PRH) and human hepatocytes (PHH) in 2D-sandwich over a 7-day treatment period. Daily exposure of PRH to phenobarbital, 5-Pregnen-3β-ol-20-one-16α‑carbonitrile (PCN) or dexamethasone increased T4 clearance over the last 24 h exposure (up to 60 %, 79 % and 67 % over control, respectively) and secretion of T4-glucuronide (T4-G; up to 463, 661 and 545 pmol/10<sup>6</sup> cells over control, respectively). Effects were concentration-dependent for phenobarbital and PCN and highest at the lowest concentration for dexamethasone, while rifampicin barely affected T4 clearance and T4-G secretion. None of the compounds, at any tested concentration, affected these parameters in PHH. Additionally, mRNA expression data were consistent with the species-specific and concentration-dependent regulation of phase I <em>Cyp/CYP</em>, phase II <em>Ugt/UGT</em> and phase III <em>Mrp2/MRP2</em> pathways occurring in rat and human liver following CAR/PXR activation. T4-UGT relative activity increased in PRH only, specifically by PCN, dexamethasone and phenobarbital. The comparison of PRH and PHH responses to compounds represents an important step towards using <em>in vitro</em> methods to reduce animal testing. We recommend using relative T4-UGT activity thresholds observed in PRH as benchmarks for defining compound-related effects across species, helping determine the human relevance of thyroid effects in rodents.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"104 ","pages":"Article 106016"},"PeriodicalIF":2.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256685","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

Transcriptomic changes and mitochondrial toxicity in response to acute and repeat dose treatment with brequinar in human liver and kidney in vitro models

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-02-01 DOI: 10.1016/j.tiv.2025.106010

Tamara Meijer , Bas ter Braak , Liesanne Loonstra-Wolters , Steven J. Kunnen , Barira Islam , Ilinca Suciu , Iain Gardner , Oliver Hatley , Richard Currie , Barry Hardy , Marcel Leist , Bob van de Water , Paul Jennings , Anja Wilmes

The potent dihydroorotate dehydrogenase (DHODH) inhibitor brequinar has been investigated as an anticancer, immunosuppressive, and antiviral pharmaceutical agent. However, its toxicity is still poorly understood. We investigated the cellular responses of primary human hepatocytes (PHH) and telomerase-immortalised human renal proximal tubular epithelial cells (RPTEC/TERT1) after a single 24-h exposure up to 100 μM brequinar. Additionally, RPTEC/TERT1 cells underwent repeated daily exposure for five consecutive days at 0.3, 3, and 20 μM. Transcriptomic analysis revealed that PHH were less sensitive to brequinar treatment than RPTEC/TERT1 cells. Upregulation of various phase I and II drug-metabolising enzymes, particularly Cytochrome P450 (CYP) 1 A and 3 A enzymes, in PHH suggests potential detoxification. Furthermore, brequinar exposure led to a significant upregulation of several stress response pathways in PHH and RPTEC/TERT1 cells, including the unfolded protein response, Nrf2, p53, and inflammatory responses. RPTEC/TERT1 cells exhibited greater sensitivity to brequinar at 0.3 μM with repeated exposure compared to a single exposure. Furthermore, brequinar could impair the mitochondrial respiration of RPTEC/TERT1 cells after 24 h. This study provides new insights into the differential responses of PHH and RPTEC/TERT1 cells in response to brequinar exposure and highlights the biological relevance of implementing repeated dosing regimens in in vitro studies.

{"title":"Transcriptomic changes and mitochondrial toxicity in response to acute and repeat dose treatment with brequinar in human liver and kidney in vitro models","authors":"Tamara Meijer , Bas ter Braak , Liesanne Loonstra-Wolters , Steven J. Kunnen , Barira Islam , Ilinca Suciu , Iain Gardner , Oliver Hatley , Richard Currie , Barry Hardy , Marcel Leist , Bob van de Water , Paul Jennings , Anja Wilmes","doi":"10.1016/j.tiv.2025.106010","DOIUrl":"10.1016/j.tiv.2025.106010","url":null,"abstract":"<div><div>The potent dihydroorotate dehydrogenase (DHODH) inhibitor brequinar has been investigated as an anticancer, immunosuppressive, and antiviral pharmaceutical agent. However, its toxicity is still poorly understood. We investigated the cellular responses of primary human hepatocytes (PHH) and telomerase-immortalised human renal proximal tubular epithelial cells (RPTEC/TERT1) after a single 24-h exposure up to 100 μM brequinar. Additionally, RPTEC/TERT1 cells underwent repeated daily exposure for five consecutive days at 0.3, 3, and 20 μM. Transcriptomic analysis revealed that PHH were less sensitive to brequinar treatment than RPTEC/TERT1 cells. Upregulation of various phase I and II drug-metabolising enzymes, particularly Cytochrome P450 (CYP) 1 A and 3 A enzymes, in PHH suggests potential detoxification. Furthermore, brequinar exposure led to a significant upregulation of several stress response pathways in PHH and RPTEC/TERT1 cells, including the unfolded protein response, Nrf2, p53, and inflammatory responses. RPTEC/TERT1 cells exhibited greater sensitivity to brequinar at 0.3 μM with repeated exposure compared to a single exposure. Furthermore, brequinar could impair the mitochondrial respiration of RPTEC/TERT1 cells after 24 h. This study provides new insights into the differential responses of PHH and RPTEC/TERT1 cells in response to brequinar exposure and highlights the biological relevance of implementing repeated dosing regimens in in vitro studies.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"104 ","pages":"Article 106010"},"PeriodicalIF":2.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123978","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