The Molecular Mechanism of Alternative P450-Catalyzed Metabolism of Environmental Phenolic Endocrine-Disrupting Chemicals

Li Ji, Shujing Ji, Chenchen Wang, Kasper Planeta Kepp*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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Abstract

Understanding the bioactivation mechanisms to predict toxic metabolites is critical for risk assessment of phenolic endocrine-disrupting chemicals (EDCs). One mechanism involves ipso-substitution, which may contribute to the total turnover of phenolic EDCs, yet the detailed mechanism and its relationship with other mechanisms are unknown. We used density functional theory to investigate the P450-catalyzed ipso-substitution mechanism of the prominent xenoestrogen bisphenol A. The ipso-substitution proceeds via H-abstraction from bisphenol A by Compound I, followed by essentially barrierless OH-rebound onto the ipso-position forming a quinol, which can spontaneously decompose into the carbocation and hydroquinone. This carbocation can further evolve into the highly estrogenic hydroxylated and dimer-type metabolites. The H-abstraction/OH-rebound reaction mechanism has been verified as a general reaction mode for many other phenolic EDCs, such as bisphenol analogues, alkylphenols and chlorophenols. The identified mechanism enables us to effectively distinguish between type I (eliminating-substituent as anion) and type II (eliminating-substituent as cation) ipso-substitution in various phenolic EDCs. We envision that the identified pathways will be applicable for prediction of metabolites from phenolic EDCs whose fate is affected by this alternative type of P450 reactivity, and accordingly enable the screening of these metabolites for endocrine-disrupting activity.
Original languageEnglish
JournalEnvironmental Science and Technology
Number of pages10
ISSN0013-936X
DOIs
Publication statusPublished - 2018

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