title: A computational approach predicting CYP450 metabolism and estrogenic activity of an endocrine disrupting compound (PCB-30).
abstract: Endocrine disrupting chemicals 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 endocrine disrupting chemical activity of unmodified compounds, but approaches predicting activity following metabolism are lacking. The present study uses a well-known environmental contaminant, PCB-30 (2,4,6-trichlorobiphenyl), as a prototype endocrine disrupting chemical and integrates predictive (computational) and experimental methods to determine its metabolic transformation by cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (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). Gas chromatography-mass spectrometry 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 endocrine disrupting chemicals involved in similar pathways.
authors.affiliation: Genome Science and Technology Graduate School, University of Tennessee, Knoxville, Tennessee, USA; Center for Molecular Biophysics, University of Tennessee/Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Harris
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Eldridge
authors.forename: Gary
authors.initials: G
authors.lastname: Sayler
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Menn
authors.forename: Alice C
authors.initials: AC
authors.lastname: Layton
authors.forename: Jerome
authors.initials: J
authors.lastname: Baudry
mesh_terms: D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D052244:Endocrine Disruptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D062105:Molecular Docking Simulation; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; C102834:2,4,6-trichlorobiphenyl; D011078:Polychlorinated Biphenyls; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: 2,4,6-trichlorobiphenyl (TCBP); Cytochrome P450 2D6 (CYP2D6); Cytochrome P450 3A4 (CYP3A4); Endocrine disrupting compound; Polychlorinated biphenyl 30 (PCB-30)