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.