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.

中文翻译：

---

亚硝胺致突变机制及其与啮齿类动物致癌效力的关系

我们进行了彻底的文献综述，以了解N-亚硝胺转化途径与啮齿动物的致突变潜力和致癌效力之间的关系。经验和计算证据表明，常见的自由基中间体是通过 CYP 介导的 α-碳夺氢产生的；它负责激活，导致 DNA 反应性重氮物质的形成，以及通过脱亚硝化而失活。CYP 代谢存在竞争位点（例如，β-碳），并且在初始生物活化后可以形成其他活性物质，尽管这些替代途径往往会降低而不是增强致癌效力。活化途径，氧化脱烷基化，是药物代谢中的常见反应，并且证据表明羰基副产物，例如甲醛，不会导致N-亚硝胺的毒性。一氧化氮 (NO) 是脱亚硝化的副产物，根据作为 NO 供体的物质的致癌性数据，它同样可以被视为N -亚硝胺毒性的增强剂。然而，并非所有N-亚硝胺都是强效啮齿动物致癌物。在大量情况下，与不在关注队列（CoC）中的非N-亚硝胺致癌物存在效力重叠；包括黄曲霉毒素样、 N-亚硝基-和烷基偶氮在内的高效啮齿动物致癌物化合物），而其他N-亚硝胺则没有致癌潜力。在这种情况下，正如 ICH M7 (R2) (2023) 指南中所提出的，致突变性是致癌性的有用替代指标。因此，在药物中N-亚硝胺的安全评估和控制中，了解致突变性机制和结构-活性关系的互补属性非常重要，这些属性会转化为效力升高，而不是与减少或缺乏相关的效力。 ，致癌效力。