Metabolic Activation

Abstract

PAHs are metabolized by various drug-metabolizing enzymes within the body. Although xenobiotic metabolism is an essential physiological function for environmental chemical detoxification, it is possible that reactive metabolic intermediates are formed in some cases. For instance, metabolism of PAHs generates hydroxylated PAHs (OHPAHs) and PAH quinones (PAHQs), which respectively have estrogenic/antiestrogenic and oxidative stress activities. These metabolites have some functional groups, such as -OH and = O, and OHPAHs and PAHQs have numerous isomers. Previous reports show that these isomers have different degrees of toxicity. Therefore, we investigated the structural activity relationships between the position of functional groups and biological activities and show that several physical parameters such as L/B ratios and O-H distances contribute to the estrogenic/ antiestrogenic activities of OHPAHs. In addition, these activities mainly depend on the position of substituted groups rather than on the kinds of functional groups. On the other hand, we found the structural activity relationship for PAHQs in the experiments measuring oxidative stress, cell viability, and ROS generation and show that ortho-PAHQs have stronger potential for ROS generation than para-PAHQs. These data suggest that the structural activity relationships of PAH derivatives could be roughly predicted from their physical parameters.