John Wiley & Sons, Ltd.

A computational approach predicting CYP450 metabolism and estrogenic activity of an endocrine disrupting compound (PCB‐30)

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Endocrine disrupting chemicals (EDCs) influence growth and development through interactions with the hormone system, often through binding to hormone receptors such as the estrogen receptor. Computational methods can predict EDC activity of unmodified compounds, but approaches predicting activity following metabolism are lacking. This study uses a well‐known environmental contaminant, PCB‐30 (2,4,6‐trichlorobiphenyl), as a prototype EDC and integrates predictive (computational) and experimental methods to determine its metabolic transformation by CYP3A4 and CYP2D6 into estrogenic byproducts. Computational predictions suggest that hydroxylation of PCB‐30 occurs at the 3‐ or 4‐phenol positions and leads to metabolites that bind more strongly than the parent molecule to the human estrogen receptor alpha (hER‐α). GC/MS experiments confirmed that the primary metabolite for CYP3A4 and CYP2D6 is 4‐hydroxy‐PCB‐30, and the secondary metabolite is 3‐hydroxy‐PCB‐30. Cell‐based bioassays (bioluminescent yeast expressing hER‐α) confirmed that hydroxylated metabolites are more estrogenic than PCB‐30. These experimental results support the applied model's ability to predict the metabolic and estrogenic fate of PCB‐30, which could be used to identify other EDCs involved in similar pathways. Environ Toxicol Chem © 2014 SETAC

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