Predicting toxicity of chemicals resulting from their metabolic activation
TIMES (tissue metabolism simulator) is a heuristic algorithm used to generate plausible metabolic maps from a comprehensive library of biotransformations and abiotic reactions. It allows prioritization of chemicals according to the toxicity of their metabolites. The list of transformations is prioritized on the basis of estimated system-specific probabilities of occurrence of these transformations. Additionally, the reliability of generated pathways, metabolites and maps was assessed according to the extent they had been supported by observed metabolism data. Hence, besides metabolites, one could also prioritize competing metabolic pathways according to their probability of occurrence and reliability. The reliability estimates could facilitate the strategic selection of chemicals for testing in order to expand the domain of the simulator most effectively. The ability of TIMES to predict in the same interface the metabolism of chemicals and toxicity resulting from their metabolic activation is an important advantage of the method. Presently, the TIMES platform is used to predict skin sensitization, mutagenicity, chromosomal aberrations and micronucleus formation taking into account the metabolic activation of chemicals. Some kinetic models are also available in the TIMES. Apart from genotoxicity the systems allows prediction of hormonal toxicity. Presently it includes models for predicting ER/AR and AhR binding affinities.
Some of the important functionalities in the system are related to: searching of chemicals with experimental data and/or observed metabolism; estimation of the metabolic similarity between chemicals taking into account different similarity criteria; providing theoretical and/or experimental support to the adequacy of the simulated metabolic pathways/metabolites; grouping of chemicals, etc.
Video clips demonstrating the main functionalities and features available in TIMES: