School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, L3 3AF, United Kingdom.
Mutat Res. 2012 Mar 18;743(1-2):10-9. doi: 10.1016/j.mrgentox.2011.12.029. Epub 2012 Jan 12.
The need to assess the ability of a chemical to act as a mutagen is one of the primary requirements in regulatory toxicology. Several pieces of legislation have led to an increased interest in the use of in silico methods, specifically the formation of chemical categories and read-across for the assessment of toxicological endpoints. One of the key steps in the development of chemical categories for mutagenicity is defining the mechanistic organic chemistry associated with the formation of a covalent bond between DNA and an exogenous chemical. To this end this study has analysed, by use of a large set of mutagenicity data (Ames test), the mechanistic coverage of a recently published set of in silico structural alerts developed for category formation. The results show that the majority of chemicals with a positive result in the Ames test were assigned at least one covalent binding mechanism related to the formation of a DNA adduct. The remaining chemicals with positive data in the Ames assay were subjected to a detailed mechanistic analysis from which 26 new structural alerts relating to covalent binding mechanisms were developed. In addition, structural alerts for radical and non-covalent intercalation mechanisms were also defined. The structural alerts outlined in this study are not intended to predict mutagenicity but rather to identify mechanisms associated with covalent and non-covalent DNA binding. This mechanistic profiling information can then be used to form chemical categories suitable for filling data gaps via read-across. A strategy for chemical category formation for mutagenicity is also presented.
评估化学物质是否具有致突变性的能力是监管毒理学的主要要求之一。有几项法规的出台增加了人们对使用计算方法的兴趣，特别是用于评估毒理学终点的化学分类和外推法。致突变性化学分类开发的关键步骤之一是确定与 DNA 和外源性化学物质之间形成共价键相关的有机化学机制。为此，本研究通过使用大量致突变性数据（Ames 试验），分析了最近发表的一组用于分类形成的计算结构警报的机制覆盖范围。结果表明，大多数在 Ames 试验中呈阳性结果的化学物质至少与形成 DNA 加合物相关的一种共价结合机制有关。Ames 测定中具有阳性数据的其余化学品进行了详细的机制分析，从中开发了 26 种与共价结合机制相关的新结构警报。此外，还定义了自由基和非共价嵌入机制的结构警报。本研究中概述的结构警报并非旨在预测致突变性，而是旨在识别与共价和非共价 DNA 结合相关的机制。然后，可以使用这种机制分析信息来形成适合通过外推法填补数据空白的化学分类。还提出了一种致突变性化学分类形成策略。
