Skin sensitization: modeling based on skin metabolism simulation and formation of protein conjugates

A quantitative structure-activity relationship (QSAR) system for estimating skin sensitization potency has been developed that incorporates skin metabolism and considers the potential of parent chemicals and/or their activated metabolites to react with skin proteins. A training set of diverse chemicals was compiled and their skin sensitization potency assigned to one of three classes. These three classes were, significant, weak, or nonsensitizing. Because skin sensitization potential depends upon the ability of chemicals to react with skin proteins either directly or after appropriate metabolism, a metabolic simulator was constructed to mimic the enzyme activation of chemicals in the skin. This simulator contains 203 hierarchically ordered spontaneous and enzyme controlled reactions. Phase I and phase II metabolism were simulated by using 102 and 9 principal transformations, respectively. The covalent interactions of chemicals and their metabolites with skin proteins were described by 83 reactions that fall within 39 alerting groups. The SAR/QSAR system developed was able to correctly classify about 80% of the chemicals with significant sensitizing effect and 72% of nonsensitizing chemicals. For some alerting groups, three-dimensional (3D)-QSARs were developed to describe the multiplicity of physicochemical, steric, and electronic parameters. These 3D-QSARs, so-called pattern recognition-type models, were applied each time a latent alerting group was identified in a parent chemical or its generated metabolite(s). The concept of the mutual influence amongst atoms in a molecule was used to define the structural domain of the skin sensitization model. The utility of the structural model domain and the predictability of the model were evaluated using sensitization potency data for 96 chemicals not used in the model building. The TIssue MEtabolism Simulator (TIMES) software was used to integrate a skin metabolism simulator and 3D-QSARs to evaluate the reactivity of chemicals thus predicting their likely skin sensitization potency.