Evidence map›Paper›PMID 39433234›Full record

ArticleRegulatory toxicology and pharmacology : RTP2024

Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells.

Xilin Li, Yuan Le, Xiaoqing Guo, Sruthi T King, Robert T Dorsam, Aisar H Atrakchi, Timothy J McGovern, Karen L Davis-Bruno, David A Keire, Robert H Heflich and 1 more

Abstract read
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In one paragraph

Article in Regulatory toxicology and pharmacology : RTP, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Article
  2. Article
  3. Complex versus simpleScience advances · 2026
    Article
  4. Article
  5. Article
  6. 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 · 2025
    Article
  7. Review
  8. Mutation accumulation following extended exposure of human HepaRG cells to a genotoxic carcinogen.Journal of environmental science and health. Part C, Toxicology and carcinogenesis · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Xilin LiNational Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA. Electronic address: xilin.li@fda.hhs.gov.
Yuan LeNational Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
Xiaoqing GuoNational Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
Sruthi T KingCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Robert T DorsamCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Aisar H AtrakchiCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Timothy J McGovernCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Karen L Davis-BrunoCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
David A KeireCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Robert H HeflichNational Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
Nan MeiNational Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA. Electronic address: nan.mei@fda.hhs.gov.

Funding

Intramural FDA HHS FD999999
6 · The paper itself

Abstract

Nitrosamine drug substance-related impurities (NDSRIs) are a sub-category of N-nitrosamine drug impurities that share structural similarity to the corresponding active pharmaceutical ingredient. The mutagenicity of NDSRIs is poorly understood. We previously tested a series of NDSRIs using the Enhanced Ames Test (EAT). In this follow-up study, we further examined the genotoxicity and mutagenicity of 15 of these NDSRIs in human TK6 cells. Seven EAT-positive NDSRIs, including N-nitroso-nortriptyline, N-nitroso-fluoxetine, N-nitroso-desmethyl-diphenhydramine, N-nitroso-duloxetine, N-nitroso-lorcaserin, N-nitroso-varenicline, and N-nitroso-sertraline, induced concentration-dependent increases in micronuclei after bioactivation with hamster liver S9. These NDSRIs were also mutagenic in the TK and HPRT gene mutation assays, consistent with their positive EAT results. In the presence of hamster liver S9, the eight EAT-negative NDSRIs were negative in the micronucleus assay and negative for mutation induction. Using TK6 cells endogenously expressing a single human cytochrome P450 (CYP), we found that CYP2C19, CYP2B6, CYP2A6, and CYP3A4 are key enzymes activating the genotoxicity and mutagenicity of these NDSRIs. Overall, the hamster S9-mediated TK6 cell mutagenicity results agreed with those observed in the EAT, indicating consistency in the mutagenic responses produced by NDSRIs across different testing systems. These data support the use of EAT for hazard identification and safety assessment of NDSRIs.

Indexed as

Drug ContaminationMutagenicity TestsMutagensNitrosaminesAnimalsCell LineCricetinaeHumansMicronucleus TestsMutationMutagensNitrosaminesChromosomal damageDNA damageGene mutationHamster liver S9NDSRIsNitrosamine impurities

Identifiers

PMID39433234
PMCPMC12477663

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Registered trials

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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.