ArticleArchives of toxicology2019
Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury.
Article in Archives of toxicology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 34 citations in OpenAlex.
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- Assessing antimicrobial utilization and costs, and correlating biological markers with adverse events in ICU patients: An effort towards antimicrobial stewardship.Journal of family medicine and primary care · 2025Article
- Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques.Cell & bioscience · 2024Review
- Biomarkers of NRF2 signalling: Current status and future challenges.Redox biology · 2024Review
- Mapping Interindividual Variability of Toxicodynamics Using High-Throughput Transcriptomics and Primary Human Hepatocytes from Fifty Donors.Environmental health perspectives · 2024Article
- Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells.Journal of hazardous materials · 2024Article
- Effects of amniotic fluid on human keratinocyte gene expression: Implications for wound healing.Experimental dermatology · 2022Article
- Emerging Bioinformatics Methods and Resources in Drug Toxicology.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Evaluating adaptive stress response gene signatures using transcriptomics.Computational toxicology (Amsterdam, Netherlands) · 2021Article
- Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors.Archives of toxicology · 2021Article
- Identification of Hub Genes in Patients with Alzheimer Disease and Obstructive Sleep Apnea Syndrome Using Integrated Bioinformatics Analysis.International journal of general medicine · 2021Article
- Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience.Archives of toxicology · 2020Article
- Nrf2 in liver toxicology.Archives of pharmacal research · 2020Review
- The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich's Ataxia.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
Abstract
The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI. Here, microarray analysis identified 108 transcripts (including several putative novel NRF2-regulated genes) that were both downregulated by siRNA targeting NRF2 and upregulated by siRNA targeting KEAP1 in PHH. Applying weighted gene co-expression network analysis (WGCNA) to transcriptomic data from the Open TG-GATES toxicogenomics repository (representing PHH exposed to 158 compounds) revealed four co-expressed gene sets or 'modules' enriched for these and other NRF2-associated genes. By classifying the 158 TG-GATES compounds based on published evidence, and employing the four modules as network perturbation metrics, we found that the activation of NRF2 is a very good indicator of the intrinsic biochemical reactivity of a compound (i.e. its propensity to cause direct chemical stress), with relatively high sensitivity, specificity, accuracy and positive/negative predictive values. We also found that NRF2 activation has lower sensitivity for the prediction of clinical DILI risk, although relatively high specificity and positive predictive values indicate that false positive detection rates are likely to be low in this setting. Underpinned by our comprehensive analysis, activation of the NRF2 network is one of several mechanism-based components that can be incorporated into holistic systems toxicology models to improve mechanistic understanding and preclinical prediction of DILI in man.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.