干旱区生态环境知识资源中心

Modeling the potential of chemicals to induce chromosomal damage has been hampered by the diversity of mechanisms which condition this biological effect. The direct binding of a chemical to DNA is one of the underlying mechanisms that is also responsible for bacteria] mutagenicity. Disturbance of DNA synthesis due to inhibition of topoisomerases and interaction of chemicals with nuclear proteins associated with DNA (e.g., histone proteins) were identified as additional mechanisms leading to chromosomal aberrations (CA). A comparative analysis of in vitro genotoxic data for a large number of chemicals revealed that more than 80% of chemicals that elicit bacterial mutagenicity (as indicated by the Ames test) also induce CA; alternatively, only 60% of chemicals that induce CA have been found to be active in the Ames test. In agreement with this relationship, a battery of models is developed for modeling CA. It combines the Ames model for bacterial mutagenicity, which has already been derived and integrated into the Optimized Approach Based on Structural Indices Set (OASIS) tissue metabolic simulator (TIMES) platform, and a newly derived model accounting for additional mechanisms leading to CA. Both models are based on the classical concept of reactive alerts. Some of the specified alerts interact directly with DNA or nuclear proteins, whereas others are applied in a combination of two- or three-dimensional quantitative structure-activity relationship models assessing the degree of activation of the alerts from the rest of the molecules. The use of each of the alerts has been justified by a mechanistic interpretation of the interaction. In combination with a rat liver S9 metabolism simulator, the model explained the CA induced by metabolically activated chemicals that do not elicit activity in the parent form. The model can be applied in two ways: with and without metabolic activation of chemicals.