Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, West Yorkshire, LS11 5PS, UK.
Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, West Yorkshire, LS11 5PS, UK.
Regul Toxicol Pharmacol. 2023 Sep;143:105460. doi: 10.1016/j.yrtph.2023.105460. Epub 2023 Jul 24.
Mutagenicity data is a core component of the safety assessment data required by regulatory agencies for acceptance of new drug compounds, with the OECD-471 bacterial reverse mutation (Ames) assay most widely used as a primary screen to assess drug impurities for potential mutagenic risk. N-Nitrosamines are highly potent mutagenic carcinogens in rodent bioassays and their recent detection as impurities in pharmaceutical products has sparked increased interest in their safety assessment. Previous literature reports indicated that the Ames test might not be sensitive enough to detect the mutagenic potential of N-nitrosamines in order to accurately predict a risk of carcinogenicity. To explore this hypothesis, public Ames and rodent carcinogenicity data pertaining to the N-nitrosamine class of compounds was collated for analysis. Here we present how variations to the OECD 471-compliant Ames test, including strain, metabolic activation, solvent type and pre-incubation/plate incorporation methods, may impact the predictive performance for carcinogenicity. An understanding of optimal conditions for testing of N-nitrosamines may improve both the accuracy and confidence in the ability of the Ames test to identify potential carcinogens.
致突变性数据是监管机构接受新药物化合物所需的安全性评估数据的核心组成部分，OECD-471 细菌回复突变（Ames）试验最常用于作为主要筛选方法，以评估药物杂质是否存在潜在的致突变风险。N-亚硝胺类物质在啮齿动物生物测定中是非常有效的致突变性致癌物质，最近在药物产品中检测到它们作为杂质，这引起了人们对其安全性评估的兴趣增加。以前的文献报道表明，Ames 试验可能不够敏感，无法检测 N-亚硝胺类物质的致突变潜力，从而无法准确预测致癌风险。为了探索这一假设，我们对与 N-亚硝胺类化合物相关的公共 Ames 和啮齿动物致癌性数据进行了整理和分析。在此，我们介绍了 OECD 471 合规性 Ames 试验中的变化，包括菌株、代谢活化、溶剂类型和预孵育/平板掺入方法，如何影响致癌性的预测性能。了解 N-亚硝胺类物质的最佳测试条件可能会提高 Ames 试验识别潜在致癌物的准确性和可信度。
