Use of the HSAB principle in quantitative structure–activity relationships in toxicological research: Application to the genotoxicity of chlorinated hydrocarbons
✍ Scribed by A. Baeten; M. Tafazoli; M. Kirsch-Volders; P. Geerlings
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 143 KB
- Volume
- 74
- Category
- Article
- ISSN
- 0020-7608
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✦ Synopsis
In the field of genotoxicology, quantitative structure᎐activity Ž . relationships QSAR are frequently used to study the relationship between the structure of a toxic chemical and its biological activity. Nowadays, quantum chemical methods are often used to obtain relevant descriptors for the compound properties which are used in their turn to set up the QSAR equations. However, studies usually are restricted to the chemicals themselves and do not consider the metabolites formed, which in most cases are the real toxic agents. The work proposed here is a sequel to a QSAR-study on the genotoxicity of some 10 chlorinated hydrocarbons performed by us earlier. It was seen that there existed a relationship between the genotoxicity of the chemicals and the energy of their LUMO orbital, confirming the reductive activation metabolism by glutathione S-transferase for these chemicals suggested in the literature. Here, the episulfonium metabolites formed through this reaction path were considered. Their interaction energy with the DNA-base guanine was calculated using a density functional theory based hard and soft acids and bases approach. It was found that this interaction energy could explain the genotoxicity sequence, which had been experimentally obtained.