Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

• DOI: 10.1021/acs.chemrestox.3c00327
• Publication Date: 2024-02-05T22:32:43Z
• Authors: David J. Snodin; Alejandra Trejo-M...; David J. Ponting; Graham F. Smith; Andreas Czich; Kevin Cross; Laura Custer; Joanne Elloway; Nigel Greene; Amit S. Kalgutkar; Susanne A. Stalford; Rachael E. Tennant; Esther Vock; Adam Zalewski; Verena Ziegler; Krista L. Dobo
• Keywords: Nitrosamine

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