Differences between in vitro and in vivo genotoxicity due to metabolism: The role of kinetics

Traditional QSAR models predict mutagenicity solely based on structural alerts for the interaction of parent chemicals or their metabolites with target macromolecules. In the present work, it is demonstrated that the presence of an alert is necessary to identify damage but it is not always sufficient to assess mutagenic potential. This is addressed by accounting for the kinetics of simulating metabolism and formation of adducts with macromolecules. The mutagenic potential of chemicals is related to the degree to which selected macromolecules are altered. This extent is estimated by the amount of formed DNA/protein adducts. Here the effect of modelling kinetic factors is investigated for chemicals having documented in vitro negative and in vivo positive data in mutagenicity and clastogenicity tests of similar capacity - in vitro Ames vs in vivo TGR and in vitro CA vs in vivo MN tests. Two factors justify the conflict in mutagenicity data: the differences in enzyme expression in the in vitro vs in vivo metabolism and the difference in exposure time for in vitro and in vivo tests. Addressing these factors required simulating the formation of DNA/protein adducts and introducing empirically-defined thresholds for the amounts of the adducts leading to mutagenic potential.