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

摘要: Endocrine disrupting chemicals influence growth and development through interactions with the hormone system, often binding to receptors such as estrogen receptor. Computational methods can predict endocrine chemical activity of unmodified compounds, but approaches predicting following metabolism are lacking. The present study uses a well-known environmental contaminant, PCB-30 (2,4,6-trichlorobiphenyl), prototype integrates predictive (computational) experimental determine its metabolic transformation by cytochrome P450 3A4 (CYP3A4) 2D6 (CYP2D6) into estrogenic byproducts. predictions suggest that hydroxylation occurs at 3- or 4-phenol positions leads metabolites bind more strongly than parent molecule human receptor alpha (hER-α). Gas chromatography–mass spectrometry experiments confirmed primary metabolite for CYP3A4 CYP2D6 is 4-hydroxy-PCB-30, secondary 3-hydroxy-PCB-30. Cell-based bioassays (bioluminescent yeast expressing hER-α) hydroxylated PCB-30. These results support applied model's ability fate PCB-30, which could be used identify other involved in similar pathways. Environ Toxicol Chem 2014;33:1615–1623. © 2014 SETAC