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N-Nitroso Compounds: Biological and Environmental Significance and Defense Mechanisms
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N-Nitroso Compounds: Biological and Environmental Significance and Defense Mechanisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 26608

Special Issue Editors

Prof. Dr. Bernd Kaina

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Guest Editor
Institute of Toxicology, University of Mainz, Mainz, Germany
Interests: DNA repair; MGMT; tumour therapy; alkylating agents; apoptosis; anticancer drugs
Special Issues, Collections and Topics in MDPI journals
Dr. Roland Frötschl

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Guest Editor
BfArM-Bundesinstitut für Arzneimittel und Medizinprodukte, Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany
Interests: mutagenicity; mode of action; quantitative analysis of genetic toxicity data; DNA repair; mechanisms of carcinogenesis; adverse outcome pathways; risk assessment
Dr. George Johnson

E-Mail Website
Guest Editor
Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK
Interests: mutagenicity; dose response modelling; risk assessment

Special Issue Information

Dear Colleagues,

N-nitroso compounds, such as N-nitrosamines, are widely distributed environmental mutagens and carcinogens. They are present in tobacco smoke and even in smoke-less tobacco, in food and beverages, in diesel exhaust and in industrial fumes. N-nitrosamines can be formed in chemical synthesis and natural biochemical processes. Certain N-nitrosamines have also been detected as impurities in some pharmaceutical products and remain a high-priority group of compounds for human health risk assessment globally. Because of their cytotoxic properties, N-nitroso compounds are used in cancer therapy. N-nitrosamines are metabolised, and reactive species can be formed that damage the DNA. Therefore, scavenging mechanisms, DNA repair and damage responses are important defence mechanisms, modulating the dose response of these substances. Whether these mechanisms potentially lead to thresholds of N-nitrosamines at low levels of mutagens/carcinogens is currently highly debated and awaiting experimental proof. This Special Issue invites contributions in the form of reviews or research papers, focused on this important topic of genetic, medical and environmental toxicology.

Prof. Dr. Bernd Kaina
Dr. Roland Frötschl
Dr. George Johnson
Guest Editors

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Keywords

  • N-nitroso compounds
  • N-nitrosamines
  • carcinogens
  • environmental mutagens

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Published Papers (4 papers)

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Research

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16 pages, 3617 KiB  
Article
Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues
by Norah A. Owiti, Joshua J. Corrigan, Lee J. Pribyl, Jennifer E. Kay and Bevin P. Engelward
Int. J. Mol. Sci. 2022, 23(19), 11776; https://doi.org/10.3390/ijms231911776 - 4 Oct 2022
Cited by 3 | Viewed by 2553
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue N-Nitroso Compounds: Biological and Environmental Significance and Defense Mechanisms)
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Review

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34 pages, 4663 KiB  
Review
DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways
by Jörg Fahrer and Markus Christmann
Int. J. Mol. Sci. 2023, 24(5), 4684; https://doi.org/10.3390/ijms24054684 - 28 Feb 2023
Cited by 19 | Viewed by 7171
Abstract
Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. [...] Read more.
Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts. Full article
(This article belongs to the Special Issue N-Nitroso Compounds: Biological and Environmental Significance and Defense Mechanisms)
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38 pages, 7420 KiB  
Review
Metabolism and DNA Adduct Formation of Tobacco-Specific N-Nitrosamines
by Yupeng Li and Stephen S. Hecht
Int. J. Mol. Sci. 2022, 23(9), 5109; https://doi.org/10.3390/ijms23095109 - 4 May 2022
Cited by 31 | Viewed by 6437
Abstract
The tobacco-specific N-nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) always occur together and exclusively in tobacco products or in environments contaminated by tobacco smoke. They have been classified as “carcinogenic to humans” by the International Agency for Research on Cancer. [...] Read more.
The tobacco-specific N-nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) always occur together and exclusively in tobacco products or in environments contaminated by tobacco smoke. They have been classified as “carcinogenic to humans” by the International Agency for Research on Cancer. In 1998, we published a review of the biochemistry, biology and carcinogenicity of tobacco-specific nitrosamines. Over the past 20 years, considerable progress has been made in our understanding of the mechanisms of metabolism and DNA adduct formation by these two important carcinogens, along with progress on their carcinogenicity and mutagenicity. In this review, we aim to provide an update on the carcinogenicity and mechanisms of the metabolism and DNA interactions of NNK and NNN. Full article
(This article belongs to the Special Issue N-Nitroso Compounds: Biological and Environmental Significance and Defense Mechanisms)
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47 pages, 5906 KiB  
Review
Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed
by Yupeng Li and Stephen S. Hecht
Int. J. Mol. Sci. 2022, 23(9), 4559; https://doi.org/10.3390/ijms23094559 - 20 Apr 2022
Cited by 86 | Viewed by 9069
Abstract
Carcinogenic N-nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens—widely detectable in relatively low levels in food, water, cosmetics, and drugs—are well-established and powerful animal carcinogens. The electrophiles resulting from the cytochrome P450-mediated [...] Read more.
Carcinogenic N-nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens—widely detectable in relatively low levels in food, water, cosmetics, and drugs—are well-established and powerful animal carcinogens. The electrophiles resulting from the cytochrome P450-mediated metabolism of N-nitrosamines can readily react with DNA and form covalent addition products (DNA adducts) that play a central role in carcinogenesis if not repaired. In this review, we aim to provide a comprehensive and updated review of progress on the metabolic activation and DNA interactions of 10 carcinogenic N-nitrosamines to which humans are commonly exposed. Certain DNA adducts such as O6-methylguanine with established miscoding properties play central roles in the cancer induction process, whereas others have been linked to the high incidence of certain types of cancers. We hope the data summarized here will help researchers gain a better understanding of the bioactivation and DNA interactions of these 10 carcinogenic N-nitrosamines and facilitate further research on their toxicologic and carcinogenic properties. Full article
(This article belongs to the Special Issue N-Nitroso Compounds: Biological and Environmental Significance and Defense Mechanisms)
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