Using electronic theory to identify metabolites present in 17α-ethinylestradiol biotransformation pathways.

This research used electronic theory to model the biotransformation of 17α-ethinylestradiol (EE(2)) under aerobic conditions in mixed culture. The methodology involved determining the Frontier Electron Density (FED) for EE(2) and various metabolites, as well as invoking well-established degradation rules to predict transformation pathways. We show that measured EE(2) metabolites are in good agreement with what is expected based on FED-based modeling. Initiating reactions occur at Ring A, producing metabolites that have been experimentally detected. When OH-EE(2) and 6AH-EE(2) are transformed, Ring A is cleaved before Ring B. The metabolites involved in these pathways have different estrogenic potentials, as implied by our analysis of the log P values and the hydrogen bonding characteristics. The OH-EE(2) and 6AH-EE(2) transformation pathways also show redox-induced electron rearrangement (RIER), where oxidation reactions lead to the reduction of carbon units present along the bond axis. Sulfo-EE(2) appears to be difficult to biotransform. These findings clarify theoretical and practical aspects of EE(2) biotransformation.