Predicting DNA-Reactivity of N-Nitrosamines: A Quantum Chemical Approach

Chemical Research in Toxicology, Journal Year: 2022, Volume and Issue: 35(11), P. 2068 - 2084

Published: Oct. 27, 2022

N-Nitrosamines (NAs) are a class of reactive organic chemicals that humans may be exposed to from environmental sources, food but also impurities in pharmaceutical preparations. Some NAs were identified as DNA-reactive mutagens and many those have been classified probable human carcinogens. Beyond high-potency mutagenic carcinogens need strictly controlled, low potency considered for risk assessment well. NA nitrosylated products active ingredients (APIs) often arise production processes or degradation. Most require metabolic activation ultimately become carcinogens, their can appropriately described by first-principles computational chemistry approaches. To this end, we treat NA-induced DNA alkylation series subsequent association dissociation reaction steps calculated stringently density functional theory (DFT), including α-hydroxylation, proton transfer, hydroxyl elimination, direct SN2/SNAr alkylation, competing hydrolysis SN1 reactions. Both toxification detoxification reactions considered. The modeled DFT at high level with an appropriate solvent model compute Gibbs free energies the (thermodynamical effects) barriers (kinetic effects). We study congeneric aliphatic cyclic identify trends. Overall, work reveals detailed insight into mechanisms NAs, suggesting individual steric electronic factors directing rate-determining influence on formation carbenium ions ultimate pro-mutagens thus Therefore, is suggested, exemplified complex API-like 4-(N-nitroso-N-methyl)aminoantipyrine which low-potency silico prediction.

Language: Английский

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Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(23), P. 15584 - 15607

Published: Nov. 28, 2022

The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence all medicinal products. In absence rodent carcinogenicity data novel N-nitrosamines amine-containing APIs, conservative class limit 18 ng/day (based most carcinogenic N-nitrosamines) or derivation intakes (AIs) using structurally related surrogates with robust is recommended. guidance implications industry given vast number marketed drugs. this perspective, rate-limiting step N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation yield DNA-reactive diazonium carbonium ion intermediates, discussed reference selection read-across analogs derive AIs. Risk-mitigation strategies managing putative preclinical discovery setting are also presented.

Language: Английский

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Comparison of the transgenic rodent mutation assay, error corrected next generation duplex sequencing, and the alkaline comet assay to detect dose-related mutations following exposure to N-nitrosodiethylamine

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Journal Year: 2023, Volume and Issue: 891, P. 503685 - 503685

Published: Aug. 24, 2023

N-Nitrosodiethylamine (NDEA), a well-studied N-nitrosamine, was tested in rats to compare the dose-response relationship of three genotoxicity endpoints. Mutant / mutation frequencies were determined using transgenic rodent (TGR) gene assay and error corrected next generation sequencing (ecNGS) (i.e., duplex (DS)), genetic damage detected by alkaline comet assay. Big Blue® (cII Locus) animals (n = 6 per dose group) administered doses 0.001, 0.01, 0.1, 1, 3 mg/kg/day NDEA oral gavage. Samples collected for cII DS analyses following 28-days exposure days recovery. In separate study, male Sprague-Dawley (SD) same gavage two consecutive then samples A dose-related increase mutant liver but not duodenum observed TGR with resulting slightly more sensitive response, lower benchmark (BMD). addition, percent tail DNA Therefore, assays showed good utility hazard identification analysis representative N-nitrosamine comparable

Language: Английский

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Mutagenic impurities in pharmaceuticals: A critical assessment of the cohort of concern with a focus on N-nitrosamines

Regulatory Toxicology and Pharmacology, Journal Year: 2023, Volume and Issue: 141, P. 105403 - 105403

Published: April 26, 2023

Language: Английский

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Nitrosamines crisis in pharmaceuticals − Insights on toxicological implications, root causes and risk assessment: A systematic review

Journal of Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 14(5), P. 100919 - 100919

Published: Dec. 12, 2023

The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates toxicity active ingredients, drug products, excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, regulatory guidelines nitrosamines. emphasizes the molecular focusing on genotoxic, mutagenic, carcinogenic, other physiological Additionally, it addresses ongoing nitrosamine crisis, development nitrosamine-free importance sensitive detection methods precise risk evaluation. comprehensive overview will aid biologists, scientists, formulation scientists research sector, researchers involved management nitrosamine-induced promoting safer products.

Language: Английский

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