Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

• Published in: Chemical research in toxicology 2024-02, Vol.37 (2), p.181-198
• Main Authors: Snodin, David J., Trejo-Martin, Alejandra, Ponting, David J., Smith, Graham F., Czich, Andreas, Cross, Kevin, Custer, Laura, Elloway, Joanne, Greene, Nigel, Kalgutkar, Amit S., Stalford, Susanne A., Tennant, Rachael E., Vock, Esther, Zalewski, Adam, Ziegler, Verena, Dobo, Krista L.
• Format: Article
• Language: English
• Subjects: Animals; Carbon; Carcinogenesis; Carcinogens - toxicity; Humans; Mutagenicity Tests; Mutagens - toxicity; Nitrosamines - metabolism; Nitrosamines - toxicity; Rodentia - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.3c00327

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., β-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure–activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.