Regulatory Toxicology and Pharmacology最新文献

Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider.

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-25 DOI: 10.1016/j.yrtph.2025.105793

Lise I Loberg, William R Proctor, Andrew D Burdick, Annick Cauvin, Anthony M DeLise, Michelle Hemkens, Andreas M Hohlbaum, Renee Hukkanen, Alanna E Sedgwick, Dana Shuey, Doris T Zane, Katie Stamp

{"title":"Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider.","authors":"Lise I Loberg, William R Proctor, Andrew D Burdick, Annick Cauvin, Anthony M DeLise, Michelle Hemkens, Andreas M Hohlbaum, Renee Hukkanen, Alanna E Sedgwick, Dana Shuey, Doris T Zane, Katie Stamp","doi":"10.1016/j.yrtph.2025.105793","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105793","url":null,"abstract":"<p><p>Targeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ consortium working group.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105793"},"PeriodicalIF":3.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Comparison of carbonyls and tobacco-specific nitrosamines in aerosols of heated tobacco products and conventional cigarette smoke using both targeted and untargeted analytical methods

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-13 DOI: 10.1016/j.yrtph.2025.105786

Hsiang-Tsui Wang , Ping-Huai Wang , Chun-Yu Chen , Tsung-Yun Liu , Han-Hsing Tsou

{"title":"Comparison of carbonyls and tobacco-specific nitrosamines in aerosols of heated tobacco products and conventional cigarette smoke using both targeted and untargeted analytical methods","authors":"Hsiang-Tsui Wang , Ping-Huai Wang , Chun-Yu Chen , Tsung-Yun Liu , Han-Hsing Tsou","doi":"10.1016/j.yrtph.2025.105786","DOIUrl":"10.1016/j.yrtph.2025.105786","url":null,"abstract":"<div><div>Cigarette smoke (CS) exposes users to harmful substances, contributing to chronic lung diseases. Heated tobacco products (HTPs) are marketed as safer alternatives due to their lower toxicant emissions from heating rather than burning tobacco. However, HTPs may produce unique toxicants that are not found in CS. The emissions of carbonyls and tobacco-specific nitrosamines (TSNAs) were compared using targeted analysis using liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UPLC-MS/MS) and untargeted analysis with UPLC-QToF and Progenesis® QI software. Targeted analysis revealed that HTP aerosol emissions contain significantly lower levels of harmful compounds compared to CS, with reductions of 8.7%–91.6% in 11 carbonyls and 85.7%–95.4% in four TSNAs) Untargeted analysis identified 25 carbonyls and seven nitrosamines in both HTPs and conventional cigarettes, with acetoin, dimethylbenzaldehyde, furfural, and diisopropanolnitrosamine (DIPN) found at relatively high levels in HTPs. While untargeted methods introduce some uncertainty, these findings underscore distinct chemical differences between HTPs and conventional cigarettes. Long-term studies are essential to fully understand the health implications of HTP use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105786"},"PeriodicalIF":3.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Accurate regulatory classification of chemical respiratory allergens: The case for robust characterisation of causation

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-12 DOI: 10.1016/j.yrtph.2025.105785

Mark A. Pemberton , Ian Kimber

{"title":"Accurate regulatory classification of chemical respiratory allergens: The case for robust characterisation of causation","authors":"Mark A. Pemberton , Ian Kimber","doi":"10.1016/j.yrtph.2025.105785","DOIUrl":"10.1016/j.yrtph.2025.105785","url":null,"abstract":"<div><div>Occupational health standards, worker safety and effective regulatory classification relies upon characterisation of occupational asthma and discrimination between allergic asthma, irritant-induced asthma, and work-exacerbated asthma, and the accurate identification of chemical allergens of the respiratory tract.</div><div>No <em>in silico, in vitro or in vivo</em> experimental method can, either alone or in combination, accurately identify chemical respiratory allergens and provide a sound basis for regulatory classification. Measurement of IgE antibody and skin prick testing can characterise allergy to proteins, but not to chemical respiratory allergens.</div><div>Therefore, characterisation of causation and accurate regulatory classification of work-related asthma relies upon characterisation of clinical and workplace histories and specific inhalation challenge tests conforming to current guidelines and best practice.</div><div>This manuscript reviews the important of accurate characterisation of causation in cases of work-related asthma to ensure accurate classification and robust regulation, and to promote a sound basis for clinical and experimental research. Commentaries on selected clinical case studies are provided that highlight key issues that confound attribution of causation. Specific recommendations are made regarding the design, conduct and interpretation of clinical investigations of work-related asthma that could provide a basis of more robust regulatory practice, and the more reliable identification of chemical respiratory allergens.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105785"},"PeriodicalIF":3.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Applicability of the in vitro skin irritation methods (EpiSkin™, EpiDerm™ SIT) to organosilicon-based substances

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-07 DOI: 10.1016/j.yrtph.2025.105778

Carole Forlini , Farah Koraichi-Emeriau , Barbara G. Schmitt , Wendy Koch , Shawn Seidel , Eckart Gura , Michael Haack , Dorothea Eigler

{"title":"Applicability of the in vitro skin irritation methods (EpiSkin™, EpiDerm™ SIT) to organosilicon-based substances","authors":"Carole Forlini , Farah Koraichi-Emeriau , Barbara G. Schmitt , Wendy Koch , Shawn Seidel , Eckart Gura , Michael Haack , Dorothea Eigler","doi":"10.1016/j.yrtph.2025.105778","DOIUrl":"10.1016/j.yrtph.2025.105778","url":null,"abstract":"<div><div>It is now widely accepted that the reconstructed human epidermis models (OECD TG 439) can be used as a standalone replacement of the <em>in vivo</em> rabbit assay (OECD TG 404) to accurately predict skin irritancy. Many legislations have now introduced the legal requirement to use <em>in vitro</em> methods as the first step. The applicability of these methods to organosilicon-based substances was not evaluated during the validation of this guideline. Therefore, the aim of the current work was to assess the applicability of EpiSkin™ and EpiDerm™ SIT <em>in vitro</em> methods for organosilicons. Ten substances were evaluated, and results were compared with existing rabbit data. The data showed that both test methods failed to accurately predict the <em>in vivo</em> skin irritation potential, with predictive capacities below the minimum test guideline requirements. The two models delivered consistent results in only 60% of the cases. Several hypotheses were explored to explain this high rate of discordance without success. As EpiDerm™ SIT showed 100% sensitivity, a new stepwise testing strategy is proposed for organosilicons consisting of starting with EpiDerm™ SIT, following by EpiSkin™ in case of positive outcome. While keeping protective, this adapted strategy avoids unnecessary animal testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105778"},"PeriodicalIF":3.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits 基于历史重复剂量数据的药物中间体毒理学关注阈值的建立及其在设定健康暴露限值中的应用。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105764

Zoe Dunn , Delorice Murudzwa , Kamila Blum

{"title":"Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits","authors":"Zoe Dunn , Delorice Murudzwa , Kamila Blum","doi":"10.1016/j.yrtph.2024.105764","DOIUrl":"10.1016/j.yrtph.2024.105764","url":null,"abstract":"<div><div>Availability of toxicological data for pharmaceutical intermediates (IMs) used in the manufacture of small molecules is often limited. Scarcity of data – in particular, repeat-dose toxicity (RDT) – renders the calculation of health-based exposure limits (HBELs) problematic. Establishment of HBELs, including occupational exposure limits (OELs) and permitted daily exposures (PDEs) facilitating worker and patient safety respectively, is however essential. Historic 28-day oral rodent toxicity data was analysed for 103 GSK isolated IMs. No-observed (adverse) effect levels (NO(A)ELs) and critical effects were extracted. The 5th percentile (p05) of the NO(A)EL distribution was 15 mg/kg/day. Substance specific HBELs were calculated, selecting the NO(A)EL as the Point of Departure (PoD); 99% of IMs (n = 102) were assigned an oral PDE ≥1000 μg/day and OEL ≥100 μg/m<sup>3</sup>. A default oral PDE of 1000 μg/day and OEL of 100 μg/m<sup>3</sup> is thus proposed for IMs. Evaluation of an additional PoD – benchmark dose lower confidence limit (BMDL) – further supported the default HBELs. The default oral PDE can also serve as a threshold of toxicological concern (TTC) for IMs. Default limits can aid in setting HBELs for novel data-poor IMs, as well as supporting waiving of RDT in the future through read-across.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105764"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Evaluating dermal absorption of perfluorooctanoic acid (PFOA) and implications for other per- and polyfluoroalkyl substances (PFAS) 评估全氟辛酸（PFOA）的皮肤吸收及其对其他全氟烷基和多氟烷基物质（PFAS）的影响。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105766

Andrew Yeh , Robyn L. Prueitt , Laura E. Kerper , Barbara D. Beck

{"title":"Evaluating dermal absorption of perfluorooctanoic acid (PFOA) and implications for other per- and polyfluoroalkyl substances (PFAS)","authors":"Andrew Yeh , Robyn L. Prueitt , Laura E. Kerper , Barbara D. Beck","doi":"10.1016/j.yrtph.2024.105766","DOIUrl":"10.1016/j.yrtph.2024.105766","url":null,"abstract":"<div><div>To date, only four studies directly measured dermal absorption kinetics of perfluorooctanoic acid (PFOA) in human skin. Reported kinetic parameters spanned two to five orders of magnitude, demonstrating the need to determine the causes of variability and identify the most appropriate dermal absorption factors for use in exposure assessments. We evaluated the reliability and physiological relevance of studies that measured PFOA fractional absorption, steady-state flux (J<sub>ss</sub>), and dermal permeability coefficient (K<sub>p</sub>). We verified whether the reported kinetic parameters were measured under appropriate conditions (<em>i.e.</em>, fractional absorption under finite dose conditions, and J<sub>ss</sub> and K<sub>p</sub> under infinite dose conditions). We recommend the following values measured at the approximate pH of the skin, and in aqueous solvents or relevant consumer product matrices, for use as provisional values in PFOA exposure assessments: 1.6% fractional absorption under finite dose conditions, and 0.132 μg/cm<sup>2</sup>-hr and 0.000044 cm/h for J<sub>ss</sub> and K<sub>p</sub>, respectively, under infinite dose conditions. Using the recommended absorption factors, we estimated PFOA exposures in children from soil and water <em>via</em> dermal and ingestion routes. Our results indicate low dermal absorption of PFOA relative to ingestion, and low dermal absorption is expected for per- and polyfluoroalkyl substances (PFAS) with physicochemical properties similar to PFOA.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105766"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Rodent estrous cycle pattern: Harmonizing the cycle evaluation and interpretation 啮齿动物发情周期模式：协调周期评价与解释。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105768

Shivakumar Holalagoudar , Susan Kisielewski , Austin Martini , Kamin Johnson , Anne-Laure Leoni , Corinna Demminger , Sonja Brosel

{"title":"Rodent estrous cycle pattern: Harmonizing the cycle evaluation and interpretation","authors":"Shivakumar Holalagoudar , Susan Kisielewski , Austin Martini , Kamin Johnson , Anne-Laure Leoni , Corinna Demminger , Sonja Brosel","doi":"10.1016/j.yrtph.2024.105768","DOIUrl":"10.1016/j.yrtph.2024.105768","url":null,"abstract":"<div><div>The estrous cycle is a sensitive endpoint from an endocrine disruptor perspective and is included in rodent reproductive toxicity studies. In this paper, the methods for estrous cycle timing and different approaches followed by testing laboratories for evaluating the days of the estrous cycle were reviewed. No major differences are identified for counting 4-day estrous cycle. However, when extended episodes of estrus (E) stages occur, the cycle counting differs between testing laboratories potentially resulting in misinterpretation and inaccurate outcome. Appearance of extended episodes of two to three E in an estrous cycle need explanation. Therefore, the following are proposed, 1) follow OECD guidance document for normal 4/5 day cycles, 2) recommends an update of the OECD document as in the current one it is unclear for a 5-day cycle ending with Proestrus(P) followed by episode(s) of estrus(E), 3) two episodes of E after P in a 5-day cycle and three consecutive episodes of E should be considered abnormal, and 4) stages prior to first E of the first cycle or after last E (last P of a 5-day) of last cycle should not be assumed a complete cycle. Additionally, call for collaboration is made to harmonize the cycle counting approach.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105768"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Exploring the link: DNA methylation and kidney injury markers in farmers exposed to glyphosate-surfactant herbicides 探索联系：暴露于草甘膦表面活性剂除草剂的农民的DNA甲基化和肾损伤标志物。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105765

Supakit Khacha-ananda, Unchisa Intayoung, Kanyapak Kohsuwan, Klintean Wunnapuk

{"title":"Exploring the link: DNA methylation and kidney injury markers in farmers exposed to glyphosate-surfactant herbicides","authors":"Supakit Khacha-ananda, Unchisa Intayoung, Kanyapak Kohsuwan, Klintean Wunnapuk","doi":"10.1016/j.yrtph.2024.105765","DOIUrl":"10.1016/j.yrtph.2024.105765","url":null,"abstract":"<div><div>Glyphosate-surfactant herbicides (GSH), widely used herbicides, have raised concerns about their potential nephrotoxic effects. Despite extensive studies, the safety of GSH remains debatable. This study aimed to determine if occupational exposure to GSH causes detectable changes in renal injury biomarkers—specifically DNA methylation, KIM-1, TIMP2, and IGFBP7—in farmers regularly exposed to these chemicals. Two urine samples, pre-task (0-h) and post-task (24-h), were collected to analyze these biomarkers. No significant immediate changes were observed post-exposure, possibly due to personal protective equipment use. Moderate positive correlations were found between IGFBP7 and KIM-1, and IGFBP7 and TIMP2, suggesting early kidney injury. About 50% of subjects had a biomarker ratio greater than 1, indicating increased levels of IGFBP7, TIMP2, and KIM-1 after GSH exposure. This indicates that farmers who regularly spray GSH are at high risk of exposure, potentially leading to significant renal injury. Further long-term studies are needed to assess the chronic effects and validate these biomarkers for monitoring renal health in populations exposed to glyphosate.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105765"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes 药品中n -亚硝胺杂质的控制：推进现行CPCA框架并支持衍生稳健的化合物特异性可接受摄入量。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105762

David J. Ponting , Andreas Czich , Susan P. Felter , Susanne Glowienke , James S. Harvey , Raphael Nudelman , Joerg Schlingemann , Stephanie Simon , Graham F. Smith , Andrew Teasdale , Robert Thomas

{"title":"Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes","authors":"David J. Ponting , Andreas Czich , Susan P. Felter , Susanne Glowienke , James S. Harvey , Raphael Nudelman , Joerg Schlingemann , Stephanie Simon , Graham F. Smith , Andrew Teasdale , Robert Thomas","doi":"10.1016/j.yrtph.2024.105762","DOIUrl":"10.1016/j.yrtph.2024.105762","url":null,"abstract":"<div><div>The carcinogenic potency categorisation approach (CPCA) has recently been introduced by health authorities. In this model, structural features from recent literature, industry proposals, and analyses performed by health authorities, provide a rapid assessment of the potential acceptable intake (AI) for a nitrosamine impurity. As with other screening regulatory values (such as the ICH M7 Threshold of Toxicological Concern), the CPCA is conservative and can be considered a <em>de minimis</em> risk management framework. In cases where a nitrosamine drug substance-related impurity (NDSRI) is present below the CPCA limit, the framework provides resolution from a toxicological perspective (i.e., no further toxicology studies are required). Where an NDSRI is above the CPCA limit, the framework provides for the initiation of additional activities (i.e., the CPCA is not the only possible limit). Read-across approaches are described in both the CPCA and M7 guidance and can provide a limit with more specific applicability than the general model. The use of available experimental data (<em>in vitro</em> or <em>in vivo</em>), is valuable in order to provide an even more specific limit. The CPCA provides a framework; however, data should permit changing the AI from initial structural assessment, based on increasing data, to ultimately increase precision of the AI.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105762"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Unraveling Caco-2 cells through functional and transcriptomic assessments 通过功能和转录组学评估揭示Caco-2细胞。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2025.105771

Ye Eun Jeong, Katherine Shea, Kevin A. Ford

{"title":"Unraveling Caco-2 cells through functional and transcriptomic assessments","authors":"Ye Eun Jeong, Katherine Shea, Kevin A. Ford","doi":"10.1016/j.yrtph.2025.105771","DOIUrl":"10.1016/j.yrtph.2025.105771","url":null,"abstract":"<div><div>The static Caco-2 monolayer is an extensively utilized model for predicting the permeability of small molecules during the drug development process. While these cells can differentiate and develop key functional and morphological features that emulate human enterocytes, they do not fully replicate the complexity of human intestinal physiology. In this study, we investigated functional and morphological aspects of Caco-2 cells, alongside their transcriptomic profiles, with a particular emphasis on genes encoding drug-metabolizing enzymes and drug transporters. We found that Caco-2 cells not only established a robust and bio-relevant permeable intestinal barrier but also demonstrated functional maturity and differentiation in the intestinal epithelium, substantiated by the activities of important enzymes and an efflux transporter. However, our targeted gene expression analyses revealed that substantial disparities were found in mRNA transcript levels among Caco-2 cells and human biopsy samples. These findings highlight that, although Caco-2 cells are valuable for assessing the passive transport of drugs, their accuracy for predicting active transport or small intestinal drug metabolism is constrained by their transcriptomic divergence from human intestinal tissues. This study highlights the importance of understanding the Caco-2 model's inherent limitations and provides insights that could inform its appropriate application in drug development and regulatory decision-making.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105771"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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