ArticleRegulatory toxicology and pharmacology : RTP2025
Genotoxicity evaluation of ten nitrosamine drug substance-related impurities using 2D and 3D HepaRG cell models.
Article in Regulatory toxicology and pharmacology : RTP, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- The in vitro alkaline comet assay with liver models as a complementary tool for genotoxicity assessment of N-nitrosamines.Archives of toxicology · 2026Article
- Differential Mutagenic Response of Rat Liver and Lung to Nicotine-Derived Nitrosamine Ketone (NNK).Chemical research in toxicology · 2026Article
- Evaluating the Suitability of HepaRG Cells for Regulatory Micronucleus Testing: Comparing Results for a Diverse Set of 28 Chemicals to Regulatory Accepted TK6 Cells.Environmental and molecular mutagenesis · 2026Article
- Complex versus simpleScience advances · 2026Article
- Mutagenicity of EAT-positive NDSRIs in HepaRG spheroids.NAM journal · 2026Article
- Development of a DNA damage assay system using stable human hepatocytes.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2026Article
- Beyond monolayers: a comparative analysis of 2D cell cultures and 3DFrontiers in bioengineering and biotechnology · 2026Review
- Determination of Nitrosamine Drug Substance-Related Impurities Derived from Nortriptyline and Sertraline Using LC-MS/MS: A Comparative Evaluation of Chromatographic Separation and Pharmaceutical Application.Pharmaceuticals (Basel, Switzerland) · 2025Article
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Authors and funding
10 authors.
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Abstract
The evaluation of nitrosamine drug substance-related impurities (NDSRIs) has become a regulatory priority due to potential carcinogenicity. Previously, we evaluated mutagenicity and genotoxicity of NDSRIs using the enhanced Ames Test (EAT) and human TK6 cells. In this study, we investigated the genotoxicity of ten of these NDSRIs using metabolically competent human HepaRG cells. DNA damage and micronucleus (MN) formation were evaluated in both 2D and 3D models using the CometChip and flow-cytometry-based MN assays, respectively. After 24-h exposure, five EAT-positive NDSRIs, N-nitroso-duloxetine, N-nitroso-fluoxetine, N-nitroso-lorcaserin, N-nitroso-nortriptyline, and N-nitroso-varenicline, significantly induced DNA damage in both 2D and 3D models and increased MN and γH2A.X formation in 3D spheroids. Only three EAT-positive NDSRIs, N-nitroso-duloxetine, N-nitroso-fluoxetine, and N-nitroso-nortriptyline, increased MN frequency in 2D cultures. The five EAT-negative NDSRIs, N-nitroso-diclofenac, N-nitroso-folic acid, N-nitroso-paroxetine, N-nitroso-desvaleryl-valsartan, and N-nitroso-desvaleryl-valsartan methyl ester, showed no DNA damage or MN formation in either model. Quantitative comparisons showed that N-nitroso-nortriptyline was the most potent genotoxicant in HepaRG cells. Overall, the ten NDSRIs exhibited the same positive/negative genotoxicity outcomes in both the EAT and 3D HepaRG spheroids. These findings support the use of 3D HepaRG spheroids as an alternative in vitro model for detecting NDSRI-induced genotoxicity and confirming NDSRI responses in the EAT.
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