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

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(9), С. 4559 - 4559

Опубликована: Апрель 20, 2022

Carcinogenic N-nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens-widely detectable relatively low levels food, water, cosmetics, drugs-are well-established powerful animal carcinogens. The electrophiles resulting from cytochrome P450-mediated metabolism N-nitrosamines can readily react with DNA form covalent addition products (DNA adducts) that play a central role carcinogenesis if not repaired. In this review, we aim to provide comprehensive updated review progress on metabolic activation interactions 10 carcinogenic which humans are commonly exposed. Certain adducts such as O6-methylguanine established miscoding properties roles cancer induction process, whereas others have been linked high incidence types cancers. We hope data summarized here will help researchers gain better understanding bioactivation these facilitate further research their toxicologic properties.

Язык: Английский

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Risk assessment of N‐nitrosamines in food

EFSA Journal, Год журнала: 2023, Номер 21(3)

Опубликована: Март 1, 2023

EFSA was asked for a scientific opinion on the risks to public health related presence of

Язык: Английский

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What is the role of nitrate/nitrite in trace organic contaminants degradation and transformation during UV-based advanced oxidation processes?

Water Research, Год журнала: 2024, Номер 253, С. 121259 - 121259

Опубликована: Фев. 5, 2024

Язык: Английский

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Multicomponent reactions (MCRs) yielding medicinally relevant rings: a recent update and chemical space analysis of the scaffolds

RSC Advances, Год журнала: 2025, Номер 15(2), С. 1447 - 1489

Опубликована: Янв. 1, 2025

We have reviewed the recently reported multicomponent reactions (MCRs) yielding cyclic frameworks in a single pot from simple building blocks under mild conditions. These MCRs may prove to be useful for drug discovery projects.

Язык: Английский

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Developing structure-activity relationships for N-nitrosamine activity

Computational Toxicology, Год журнала: 2021, Номер 20, С. 100186 - 100186

Опубликована: Сен. 8, 2021

The detection of N-nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that N-nitrosamine risk assessments be performed on all medical products [EMA/351053/2019 rev 1 (2019)]. Regulation impurity levels pharmaceutical drug substances and is described the ICH M7(R1) guideline where they are referred as "cohort-of-concern" compounds potent rodent carcinogens [Kroes et. al. 2004]. EMA, U.S. FDA other have set provisional acceptable daily intake limits for N-nitrosamines calculated from carcinogenicity TD50 values experimentally measured or close analogs. class-specific limit can adjusted based upon a structure activity relationship analysis (SAR) comparison with analogs having established data [EMA/369136/2020, (2020)]. To investigate whether improvements SARs more accurately predict carcinogenic potency, an ad hoc workgroup 23 companies universities was goals addressing scientific issues including: reporting review mutagenicity reaction mechanisms, collection available, public relevant experimental data, development structure–activity relationships consistent mechanisms prediction potency categories, improved methods calculating mechanistic Here we describe this collaboration our progress date towards mechanistically relationships. We propose improving assessment by first establishing dominant mechanism prior retrieving appropriate use read-across exercises.

Язык: Английский

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What Makes a Potent Nitrosamine? Statistical Validation of Expert-Derived Structure–Activity Relationships

Chemical Research in Toxicology, Год журнала: 2022, Номер 35(11), С. 1997 - 2013

Опубликована: Окт. 27, 2022

The discovery of carcinogenic nitrosamine impurities above the safe limits in pharmaceuticals has led to an urgent need develop methods for extending structure–activity relationship (SAR) analyses from relatively limited datasets, while level confidence required that SAR indicates there is significant value investigating effect individual substructural features a statistically robust manner. This challenging exercise perform on small dataset, since practice, compounds contain mixture different features, which may confound both expert and statistical quantitative (QSAR) methods. Isolating effects single structural feature made difficult due confounding other functionality as well issues relating determining significance cases concurrent tests large number potential variables with dataset; naïve QSAR model does not predict any be after correction multiple testing. We propose variation Bayesian linear regression estimate each simultaneously yet independently, taking into account combinations present dataset reducing impact testing, showing some have impact. method can used provide validation approaches differences potency between groupings nitrosamines. Structural lead highest lowest isolated using this method, novel assigned categories high accuracy.

Язык: Английский

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Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite

International Journal of Pharmaceutics, Год журнала: 2022, Номер 620, С. 121740 - 121740

Опубликована: Апрель 11, 2022

Since late 2019, concerns regarding trace levels of the probable human carcinogen N-dimethylnitrosamine (NDMA) in Metformin-containing pharmaceuticals have been an issue if they exceeded maximum allowable intake 96 ng/day for a medicine with long-term intake. Here, we report results from extensive analysis NDMA content along active pharmaceutical ingredient (API) manufacturing process as well two different drug product processes. Our findings confirm that Metformin API is not significant source found and created at those steps introduce heat nitrite. We demonstrate reduction nitrite excipients effective means to reduce product. Limiting residual dimethylamine has proven be another important factor control leads formation products. Furthermore, historical batches products shown may increase during storage, but reached were shelf-life limiting under study.

Язык: Английский

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Highly Selective and Sensitive Detection of Nitrite Ion by an Unusual Nitration of a Fluorescent Benzimidazole

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(5), С. 2745 - 2749

Опубликована: Янв. 30, 2023

Nitrite (NO2-) is a physiologically significant anion having implications for cellular signaling. Here we report our serendipitous discovery of highly selective fluorescence-based nitrite sensing using benzimidazole which stems from hitherto-unknown direct nitration sodium nitrite. Using one- and two-dimensional NMR techniques, elucidate the chemical structures new nitrated benzimidazoles show differences in products conventional with nitric acid. We also its utility robust nitrite-containing samples.

Язык: Английский

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Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals

Journal of Pharmaceutical Sciences, Год журнала: 2023, Номер 112(5), С. 1166 - 1182

Опубликована: Янв. 1, 2023

Язык: Английский

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DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(5), С. 4684 - 4684

Опубликована: Фев. 28, 2023

Nitrosamines occur widespread in food, drinking water, cosmetics, as well tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected impurities various drugs. This is of particular concern are alkylating agents that genotoxic carcinogenic. We first summarize the current knowledge on different sources chemical nature with a focus relevant nitrosamines. Subsequently, we present major DNA alkylation adducts induced by upon their metabolic activation CYP450 monooxygenases. then describe repair pathways engaged adducts, which include base excision repair, direct damage reversal MGMT ALKBH, nucleotide repair. Their roles protection against carcinogenic effects highlighted. Finally, address translesion synthesis tolerance mechanism to adducts.

Язык: Английский

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