Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed

Li, Yupeng; Hecht, Stephen S.

doi:10.3390/ijms23094559

Cited by 76 publications

(115 citation statements)

References 258 publications

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“…It is well established in multiple animal models that the carcinogenicity of NDMA is greatest in the liver, followed by the lungs, and then the kidneys [ 11 , 62 ]. These differences in carcinogenic potential can be partly explained by the variation of P450 expression in these organs [ 60 , 61 ], which directly correlates with cancer susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike MMS, NDMA is an indirect-acting methylating agent that requires metabolic activation by cytochrome P450-2E1 (CYP2E1) to form a DNA-reactive breakdown product, namely the methyldiazonium ion [ 8 , 9 , 10 ]. NDMA is a potent carcinogen in animal models, causing liver, lung, and kidney tumors [ 11 ], and NDMA has been found in contaminated medications and municipal water supplies [ 12 , 13 , 14 , 15 , 16 ]. More recently, NDMA was linked to a childhood cancer cluster in Wilmington, MA, and the source of the NDMA was traced to the Olin Chemical Superfund Site [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues

Owiti

Corrigan

Pribyl

et al. 2022

IJMS

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The comet assay is a versatile assay for detecting DNA damage in eukaryotic cells. The assay can measure the levels of various types of damage, including DNA strand breaks, abasic sites and alkali-sensitive sites. Furthermore, the assay can also be modified to include purified DNA glycosylases so that alkylated and oxidized bases can be detected. The CometChip is a higher throughput version of the traditional comet assay and has been used to study cultured cells. Here, we have tested its utility for studies of DNA damage present in vivo. We show that the CometChip is effective in detecting DNA damage in multiple tissues of mice exposed to the direct-acting methylating agent methylmethane sulfonate (MMS) and to the metabolically activated methylating agent N-nitrosodimethylamine (NDMA), which has been found to contaminate food, water, and drugs. Specifically, results from MMS-exposed mice demonstrate that DNA damage can be detected in cells from liver, lung, kidney, pancreas, brain and spleen. Results with NDMA show that DNA damage is detectable in metabolically competent tissues (liver, lung, and kidney), and that DNA repair in vivo can be monitored over time. Additionally, it was found that DNA damage persists for many days after exposure. Furthermore, glycosylases were successfully incorporated into the assay to reveal the presence of damaged bases. Overall, this work demonstrates the efficacy of the in vivo CometChip and reveals new insights into the formation and repair of DNA damage caused by MMS and NDMA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues

Owiti

Corrigan

Pribyl

et al. 2022

IJMS

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“…In the case of cyclic aliphatic rings, intramolecular ring closure is possible via reaction with the terminal aldehyde group (Figure 4). 19,27 Both acyclic and cyclic carbocations are known to be DNA-reactive species. 27 (DE) One potential pathway is direct DNA alkylation where the aliphatic and aromatic diazonium cations mostly react via S N 2/S N Ar mechanism with DNA, which includes N 2 elimination, because their corresponding carbenium ions are usually instable.…”

Section: ■ Computational Approach and Methodsmentioning

confidence: 99%

“…19,27 Both acyclic and cyclic carbocations are known to be DNA-reactive species. 27 (DE) One potential pathway is direct DNA alkylation where the aliphatic and aromatic diazonium cations mostly react via S N 2/S N Ar mechanism with DNA, which includes N 2 elimination, because their corresponding carbenium ions are usually instable. Alkylation of the DNA bases may occur at different nucleophilic positions (Figure 5).…”

Section: ■ Computational Approach and Methodsmentioning

confidence: 99%

“…Specifically for NPYR, its N7,8-butano-G adduct is investigated together with other adducts, since this product is the most prominent species observed in rats as a preclinical toxicology study species. 27 As a model system for DNA alkylation reactions, we employed the N7 position of guanine, which is known to be the most prominent alkylation position. 31 Both the free energies and transition states were computed for this step.…”

Section: ■ Computational Approach and Methodsmentioning

confidence: 99%

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

Wenzel¹,

Schmidt²,

Blumrich³

et al. 2022

Chem. Res. Toxicol.

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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 of those have been classified as probable human carcinogens. Beyond high-potency mutagenic carcinogens that need to be strictly controlled, NAs of low potency need to be considered for risk assessment as well. NA impurities and nitrosylated products of active pharmaceutical ingredients (APIs) often arise from production processes or degradation. Most NAs require metabolic activation to ultimately become carcinogens, and their activation can be appropriately described by first-principles computational chemistry approaches. To this end, we treat NAinduced DNA alkylation as a series of subsequent association and dissociation reaction steps that can be calculated stringently by density functional theory (DFT), including α-hydroxylation, proton transfer, hydroxyl elimination, direct S N 2/S N Ar DNA alkylation, competing hydrolysis and S N 1 reactions. Both toxification and detoxification reactions are considered. The activation reactions are modeled by DFT at a high level of theory with an appropriate solvent model to compute Gibbs free energies of the reactions (thermodynamical effects) and activation barriers (kinetic effects). We study congeneric series of aliphatic and cyclic NAs to identify trends. Overall, this work reveals detailed insight into mechanisms of activation for NAs, suggesting that individual steric and electronic factors have directing and rate-determining influence on the formation of carbenium ions as the ultimate pro-mutagens and thus carcinogens. Therefore, an individual risk assessment of NAs is suggested, as exemplified for the complex API-like 4-(N-nitroso-N-methyl)aminoantipyrine which is considered as low-potency NA by in silico prediction.

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Assessing the genotoxicity of N‐nitrosodiethylamine with three in vivo endpoints in male Big Blue® transgenic and wild‐type C57BL/6N mice

Zhang,

Coffing,

Gunther

et al. 2024

Environ and Mol Mutagen

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The detection of N‐nitrosamines in drug products has raised global regulatory interest in recent years due to the carcinogenic potential of some nitrosamines in animals and a need to identify a testing strategy has emerged. Ideally, methods used would allow for the use of quantitative analysis of dose–response data from in vivo genotoxicity assays to determine a compound‐specific acceptable intake for novel nitrosamines without sufficient carcinogenicity data. In a previous study we compared the dose–response relationships of N‐nitrosodiethylamine (NDEA) in three in vivo genotoxicity endpoints in rats. Here we report a comparison of NDEA's genotoxicity profile in mice. Big Blue® mice were administered NDEA at doses of 0.001, 0.01, 0.1, 1 and 3 mg/kg/day by oral gavage for 28 days followed by 3 days of expression. Statistically significant increases in the NDEA induced mutations were detected by both the transgenic rodent mutation assay (TGR) using the cII endpoint and by duplex sequencing in the liver but not bone marrow of mice. In addition, administration of NDEA for two consecutive days in male C57BL/6N mice caused elevated DNA damage levels in the liver as measured by % tail DNA in comet assay. The benchmark dose (BMD) analysis shows a BMDL50 of 0.03, 0.04 and 0.72 mg/kg/day for TGR, duplex sequencing and comet endpoints, respectively. Overall, this study demonstrated a similar genotoxicity profile of NDEA between mice and rats and provides a reference that can be used to compare the potential potency of other novel nitrosamines for the induction of gene mutations.

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Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed

Cited by 76 publications

References 258 publications

Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues

Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues

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

Assessing the genotoxicity of N‐nitrosodiethylamine with three in vivo endpoints in male Big Blue® transgenic and wild‐type C57BL/6N mice

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