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Evaluation of two in silico programs for predicting mutagenicity and carcinogenicity potential for 4-methylimidazole (4-MeI) and known metabolites

Abstract 4-Methylimidazole (4-MeI) is a nitrogen-containing heterocyclic compound that is used in the manufacture of chemicals, dyes and pharmaceuticals and may be found in a variety of foods following formation during heating. The purpose of this study was to use two different in silico programs, CASE Ultra and Toxtree, to investigate potential structure-activity relationships in 4-MeI and its metabolites for mutagenicity and carcinogenicity, and combine that information with the available literature to draw conclusions regarding the strength of the predictions observed. Neither CASE Ultra nor Toxtree identified any structural alerts that were associated with mutagenic activity. Data for 4-MeI from a single study were used in the development of the CASE Ultra mouse and rat carcinogenicity models, but no additional similar structures were identified in the carcinogenicity model training set. One metabolite, 5-methylhydantoin, was predicted to be positive in the CASE Ultra carcinogenicity male and female mouse models; positive predictivity percentages of 60.9% and 73.7%, respectively. However, low structural similarity between 5-methylhydantoin and the compounds identified in the training set (<25%) decreases confidence in the positive prediction. Three metabolites were predicted to be positive in the CASE Ultra mouse micronucleus model, but again suffered from low structural similarity. Both limited structural similarity and inconsistent responses among the other clastogenicity models suggest that additional structurally similar compounds are needed to assess the predictive capacity of these alerts for biological activity of these compounds.