ArticleArchives of toxicology2023
Genotoxicity assessment of eight nitrosamines using 2D and 3D HepaRG cell models.
Article in Archives of toxicology, 2023. 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.
- The in vitro alkaline comet assay with liver models as a complementary tool for genotoxicity assessment of N-nitrosamines.Archives of 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
- 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
- 3D Liver Models for Genotoxicity Testing.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Quantitative genotoxicity assessment of N-nitrosodimethylamine in mice by error-corrected next-generation sequencing and DNA methylation quantification for toxicity threshold determination.Archives of toxicology · 2025Article
- Genotoxicity evaluation of ten nitrosamine drug substance-related impurities using 2D and 3D HepaRG cell models.Regulatory toxicology and pharmacology : RTP · 2025Article
- Development of a TK6-derived cell line expressing four human cytochrome P450s for genotoxicity testing.Toxicology in vitro : an international journal published in association with BIBRA · 2025Article
- AFood science & nutrition · 2025Article
- Comparative DNA damage induced by eight nitrosamines in primary human and macaque hepatocytes.Chemico-biological interactions · 2025Article
- Integration of the rat liver micronucleus assay into a 28-day treatment protocol: testing the genotoxicity of 4 small-molecule nitrosamines with different carcinogenic potencies and tumor target specificities.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Mutation accumulation following extended exposure of human HepaRG cells to a genotoxic carcinogen.Journal of environmental science and health. Part C, Toxicology and carcinogenesis · 2025Article
- Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells.Regulatory toxicology and pharmacology : RTP · 2024Article
- Optimizing the detection of N-nitrosamine mutagenicity in the Ames test.Regulatory toxicology and pharmacology : RTP · 2024Article
- Evaluating the mutagenicity of N-nitrosodimethylamine in 2D and 3D HepaRG cell cultures using error-corrected next generation sequencing.Archives of toxicology · 2024Article
- Application of HepaRG cells for genotoxicity assessment: a review.Journal of environmental science and health. Part C, Toxicology and carcinogenesis · 2024Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
N-nitrosamine impurities have been increasingly detected in human drugs. This is a safety concern as many nitrosamines are mutagenic in bacteria and carcinogenic in rodent models. Typically, the mutagenic and carcinogenic activity of nitrosamines requires metabolic activation by cytochromes P450 enzymes (CYPs), which in many in vitro models are supplied exogenously using rodent liver homogenates. There are only limited data on the genotoxicity of nitrosamines in human cell systems. In this study, we used metabolically competent human HepaRG cells, whose metabolic capability is comparable to that of primary human hepatocytes, to evaluate the genotoxicity of eight nitrosamines [N-cyclopentyl-4-nitrosopiperazine (CPNP), N-nitrosodibutylamine (NDBA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), and N-nitrosomethylphenylamine (NMPA)]. Under the conditions we used to culture HepaRG cells, three-dimensional (3D) spheroids possessed higher levels of CYP activity compared to 2D monolayer cells; thus the genotoxicity of the eight nitrosamines was investigated using 3D HepaRG spheroids in addition to more conventional 2D cultures. Genotoxicity was assessed as DNA damage using the high-throughput CometChip assay and as aneugenicity/clastogenicity in the flow-cytometry-based micronucleus (MN) assay. Following a 24-h treatment, all the nitrosamines induced DNA damage in 3D spheroids, while only three nitrosamines, NDBA, NDEA, and NDMA, produced positive responses in 2D HepaRG cells. In addition, these three nitrosamines also caused significant increases in MN frequency in both 2D and 3D HepaRG models, while NMBA and NMPA were positive only in the 3D HepaRG MN assay. Overall, our results indicate that HepaRG spheroids may provide a sensitive, human-based cell system for evaluating the genotoxicity of nitrosamines.
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