دورية أكاديمية
Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for the Early Assessment of Drug Safety Liabilities.
| العنوان: | Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for the Early Assessment of Drug Safety Liabilities. |
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| المؤلفون: | Podtelezhnikov AA; Human Genetics and Pharmacogenomics., Monroe JJ; Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486-0004., Aslamkhan AG; Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486-0004., Pearson K; Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486-0004., Qin C; Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486-0004., Tamburino AM; Human Genetics and Pharmacogenomics., Loboda AP; Human Genetics and Pharmacogenomics., Glaab WE; Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486-0004., Sistare FD; Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486-0004., Tanis KQ; Human Genetics and Pharmacogenomics. |
| المصدر: | Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2020 May 01; Vol. 175 (1), pp. 98-112. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Cary, NC : Oxford University Press Original Publication: Orlando, FL : Academic Press, c1998- |
| مواضيع طبية MeSH: | Drug Development* , Transcriptome*, Chemical and Drug Induced Liver Injury/*etiology , Liver/*drug effects , Receptors, Cytoplasmic and Nuclear/*agonists , Transcription Factors/*agonists , Xenobiotics/*toxicity, Animals ; Chemical and Drug Induced Liver Injury/genetics ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Gene Expression Profiling ; Gene Regulatory Networks ; Liver/metabolism ; Liver/pathology ; Male ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Risk Assessment ; Signal Transduction ; Toxicity Tests ; Toxicogenetics ; Transcription Factors/genetics ; Transcription Factors/metabolism |
| مستخلص: | The robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification, and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection, and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 120 different compounds, many of which are known to be associated with clinical risk for drug-induced liver injury by diverse mechanisms. Clustering, correlation, and linear modeling analyses were used to identify and optimize coexpressed gene signatures modulated by drug treatment. Here, we specifically focused on prioritizing 9 key signatures for their pragmatic utility for routine monitoring in initial rat tolerability studies just prior to entering drug development. These signatures are associated with 5 canonical xenobiotic nuclear receptors (AHR, CAR, PXR, PPARα, ER), 3 mediators of reactive metabolite-mediated stress responses (NRF2, NRF1, P53), and 1 liver response following activation of the innate immune response. Comparing paradigm chemical inducers of each receptor to the other compounds surveyed enabled us to identify sets of optimized gene expression panels and associated scoring algorithms proposed as quantitative mechanistic biomarkers with high sensitivity, specificity, and quantitative accuracy. These findings were further qualified using public datasets, Open TG-GATEs and DrugMatrix, and internal development compounds. With broader collaboration and additional qualification, the quantitative toxicogenomic framework described here could inform candidate selection prior to committing to drug development, as well as complement and provide a deeper understanding of the conventional toxicology study endpoints used later in drug development. (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) |
| فهرسة مساهمة: | Keywords: biomarkers; gene expression/regulation; liver; methods; receptor; safety evaluation; systems; toxicogenomics; toxicology; transcription factors |
| المشرفين على المادة: | 0 (Receptors, Cytoplasmic and Nuclear) 0 (Transcription Factors) 0 (Xenobiotics) |
| تواريخ الأحداث: | Date Created: 20200303 Date Completed: 20210601 Latest Revision: 20210601 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1093/toxsci/kfaa026 |
| PMID: | 32119089 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1096-0929 |
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| DOI: | 10.1093/toxsci/kfaa026 |