ArticleToxicological sciences : an official journal of the Society of Toxicology2019
Chemical Activation of the Constitutive Androstane Receptor Leads to Activation of Oxidant-Induced Nrf2.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 38 citations in OpenAlex.
- Dose-response modeling of effects in mice after exposure to a polyfluoroalkyl substance (Nafion byproduct 2).Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: primary and secondary gene responses with links to disease progression.Toxicological sciences : an official journal of the Society of Toxicology · 2024Article
- A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling.Frontiers in toxicology · 2024Article
- Article
- Increased Cell Proliferation as a Key Event in Chemical Carcinogenesis: Application in an Integrated Approach for the Testing and Assessment of Non-Genotoxic Carcinogenesis.International journal of molecular sciences · 2023Review
- Constitutive Androstane Receptor Agonist, TCPOBOP: Maternal Exposure Impairs the Growth and Development of Female Offspring in Mice.International journal of molecular sciences · 2023Article
- Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute-on-chronic alcohol-induced liver injury.Alcoholism, clinical and experimental research · 2022Article
- A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
- Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats.Frontiers in physiology · 2022Article
- Associations of persistent organic pollutants in human adipose tissue with retinoid levels and their relevance to the redox microenvironment.Environmental research · 2021Article
- Sex-, Age-, and Race/Ethnicity-Dependent Variations in Drug-Processing and NRF2-Regulated Genes in Human Livers.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Article
- Cyp2b-null male mice are susceptible to diet-induced obesity and perturbations in lipid homeostasis.The Journal of nutritional biochemistry · 2019Article
- Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors as a First Step in Protection from Xenobiotics.Nuclear receptor research · 2019Article
- Considerations for Strategic Use of High-Throughput Transcriptomics Chemical Screening Data in Regulatory Decisions.Current opinion in toxicology · 2019Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Exposure to environmentally relevant chemicals that activate the xenobiotic receptors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor alpha (PPARα) in rodent test systems often leads to increases in oxidative stress (OS) that contributes to liver cancer induction. We hypothesized that activation of the oxidant-induced transcription factor Nrf2 could be used as a surrogate endpoint for increases in OS. We examined the relationships between activation of xenobiotic receptors and Nrf2 using previously characterized gene expression biomarkers that accurately predict modulation. Using a correlation approach (Running Fisher Test), the biomarkers were compared with microarray profiles in a mouse liver gene expression compendium. Out of the 163 chemicals examined, 47% from 53 studies activated Nrf2. We found consistent coupling between CAR and Nrf2 activation. Out of the 41 chemicals from 32 studies that activated CAR, 90% also activated Nrf2. CAR was activated earlier and at lower doses than Nrf2, indicating CAR activation preceded Nrf2 activation. Nrf2 activation by 2 CAR activators was abolished in CAR-null mice. We hypothesized that Nrf2 is activated by reactive oxygen species from the increased activity of enzymes encoded by Cyp2b family members. However, Nrf2 was similarly activated in the livers of both TCPOBOP-treated wild-type and Cyp2b9/10/13-null mice. This study provides evidence that Nrf2 activation (1) often occurs after exposure to xenobiotic chemicals, (2) is tightly linked to activation of CAR, and (3) does not require induction of 3 Cyp2b genes secondary to CAR activation.
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