ArticleArchives of toxicology2022
Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation.
Article in Archives of toxicology, 2022. 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, 24 citations in OpenAlex.
- Identifying androgen receptor antagonists using a metabolically competent high-throughput screening assay.Current research in toxicology · 2026Article
- Interpretation of in vitro concentration-response data for risk assessment and regulatory decision-making: Report from the 2022 IWGT quantitative analysis expert working group meeting.Environmental and molecular mutagenesis · 2025Review
- High-content toxicological profiling of 87 compounds using a 3D mouse mini-testis model: a New Approach Methodology (NAM) for prioritizing male reproductive toxicants.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- ICRF193 potentiates the genotoxicity of etoposide.Scientific reports · 2025Article
- Application of cytochrome P450 enzyme assays to predict p53 inducers and AChE inhibitors that require metabolic activation.Toxicology and applied pharmacology · 2025Article
- Profiling the Tox21 Compound Library for Their Inhibitory Effects on Cytochrome P450 Enzymes.International journal of molecular sciences · 2025Article
- Profiling of Environmental Mixtures Containing Metals for Their Toxicity Pathways and Mechanism of Action.Environmental science & technology · 2025Article
- Prediction of chemical-induced acute toxicity using in vitro assay data and chemical structure.Toxicology and applied pharmacology · 2024Article
- In Vitro Metabolism and p53 Activation of Genotoxic Chemicals: Abiotic CYP Enzyme vs Liver Microsomes.Chemical research in toxicology · 2024Article
- Use of Tox21 screening data to profile PFAS bioactivities on nuclear receptors, cellular stress pathways, and cytochrome p450 enzymes.Journal of hazardous materials · 2024Article
- High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions.Annual review of pharmacology and toxicology · 2024Review
- Consideration of vendor-related differences in hepatic metabolic stability data to optimize early ADME screening in drug discovery.SLAS discovery : advancing life sciences R & D · 2024Article
- In vitro profiling of pesticides within the Tox21 10K compound library for bioactivity and potential toxicity.Toxicology and applied pharmacology · 2023Article
- Development of a bioprinter-based method for incorporating metabolic competence into high-throughputFrontiers in toxicology · 2023Article
- Lestaurtinib induces DNA damage that is related to estrogen receptor activation.Current research in toxicology · 2023Article
- Use of Tox21 Screening Data to Evaluate the COVID-19 Drug Candidates for Their Potential Toxic Effects and Related Pathways.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
Currently, approximately 80,000 chemicals are used in commerce. Most have little-to-no toxicity information. The U.S. Toxicology in the 21st Century (Tox21) program has conducted a battery of in vitro assays using a quantitative high-throughput screening (qHTS) platform to gain toxicity information on environmental chemicals. Due to technical challenges, standard methods for providing xenobiotic metabolism could not be applied to qHTS assays. To address this limitation, we screened the Tox21 10,000-compound (10K) library, with concentrations ranging from 2.8 nM to 92 µM, using a p53 beta-lactamase reporter gene assay (p53-bla) alone or with rat liver microsomes (RLM) or human liver microsomes (HLM) supplemented with NADPH, to identify compounds that induce p53 signaling after biotransformation. Two hundred and seventy-eight compounds were identified as active under any of these three conditions. Of these 278 compounds, 73 gave more potent responses in the p53-bla assay with RLM, and 2 were more potent in the p53-bla assay with HLM compared with the responses they generated in the p53-bla assay without microsomes. To confirm the role of metabolism in the differential responses, we re-tested these 75 compounds in the absence of NADPH or with heat-attenuated microsomes. Forty-four compounds treated with RLM, but none with HLM, became less potent under these conditions, confirming the role of RLM in metabolic activation. Further evidence of biotransformation was obtained by measuring the half-life of the parent compounds in the presence of microsomes. Together, the data support the use of RLM in qHTS for identifying chemicals requiring biotransformation to induce biological responses.
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Registered trials
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.