ArticleJournal of pharmacological and toxicological methods
mRNA transfection retrofits cell-based assays with xenobiotic metabolism.
Article in Journal of pharmacological and toxicological methods. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 44 citations in OpenAlex.
- Development of a DNA damage assay system using stable human hepatocytes.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2026Article
- On the Utilization and Characterization of External Biotransformation Systems inACS environmental Au · 2026Review
- Testing Strategies for Metabolite-Mediated Neurotoxicity.International journal of molecular sciences · 2025Review
- Current Analytical Strategies for mRNA-Based Therapeutics.Molecules (Basel, Switzerland) · 2025Review
- Identification of neural-relevant toxcast high-throughput assay intended gene targets: Applicability to neurotoxicity and neurotoxicant putative molecular initiating events.Neurotoxicology · 2024Review
- Water Quality Monitoring with the Multiplexed Assay MitoOxTox for Mitochondrial Toxicity, Oxidative Stress Response, and Cytotoxicity in AREc32 Cells.Environmental science & technology · 2024Article
- Screening for drinking water contaminants of concern using an automated exposure-focused workflow.Journal of exposure science & environmental epidemiology · 2024Article
- New Approach Methodologies for the Endocrine Activity Toolbox: Environmental Assessment for Fish and Amphibians.Environmental toxicology and chemistry · 2023Review
- Development of a bioprinter-based method for incorporating metabolic competence into high-throughputFrontiers in toxicology · 2023Article
- High-throughput AR dimerization assay identifies androgen disrupting chemicals and metabolites.Frontiers in toxicology · 2023Article
- Mapping Mechanistic Pathways of Acute Oral Systemic Toxicity Using Chemical Structure and Bioactivity Measurements.Frontiers in toxicology · 2022Article
- Quantitative non-targeted analysis: Bridging the gap between contaminant discovery and risk characterization.Environment international · 2022Article
- High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures.NPJ systems biology and applications · 2021Article
- The Alginate Immobilization of Metabolic Enzymes Platform Retrofits an Estrogen Receptor Transactivation Assay With Metabolic Competence.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Selecting a minimal set of androgen receptor assays for screening chemicals.Regulatory toxicology and pharmacology : RTP · 2020Article
- Identifying adipogenic chemicals: Disparate effects in 3T3-L1, OP9 and primary mesenchymal multipotent cell models.Toxicology in vitro : an international journal published in association with BIBRA · 2020Article
- Identifying and Characterizing Stress Pathways of Concern for Consumer Safety in Next-Generation Risk Assessment.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Development and Application of TK6-derived Cells Expressing Human Cytochrome P450s for Genotoxicity Testing.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Potential of ToxCast Data in the Safety Assessment of Food Chemicals.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to false positive (chemical is detoxified in vivo) as well as false negative results (chemical is bioactivated in vivo) and thus potential mischaracterization of chemical hazard. To address this challenge, the ten most prevalent human liver cytochrome P450 (CYP) enzymes were introduced into a human cell line (HEK293T) with low endogenous metabolic capacity. The CYP enzymes were introduced via transfection of modified mRNAs as either singlets or as a mixture in relative proportions as expressed in human liver. Initial experiments using luminogenic substrates demonstrate that CYP enzyme activities are significantly increased when co-transfected with an mRNA encoding a CYP accessory protein, P450 oxidoreductase (POR). Transfected HEK293T cells demonstrate the ability to produce predicted metabolites following treatment with well-studied CYP substrates for at least 18 h post-treatment. As a demonstration of how this method can be used to retrofit existing HTS assays, a proof-of-concept screen for cytotoxicity in HEK293T cells was conducted using 56 test compounds. The results demonstrate that the xenobiotic metabolism conferred by transfection of CYP-encoding mRNAs shifts the dose-response relationship for some of the tested chemicals such as aflatoxin B1 (bioactivation) and fenazaquin (detoxification). Overall, transfection of CYP-encoding mRNAs is an effective and portable solution for retrofitting existing cell-based HTS assays with metabolic competence.
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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.