title: Comparative analysis of human CYP3A4 and rat CYP3A1 induction and relevant gene expression by bisphenol A and diethylstilbestrol: implications for toxicity testing paradigms.
abstract: Bisphenol A (BPA) and diethylstilbestrol (DES) are endocrine-disrupting chemicals that interact with the human pregnane X receptor (PXR). CYP3A4 enzyme is essential in the hydroxylation of steroid hormones and is regulated by PXR. In the present study, human and rat hepatoma cell lines were exposed to BPA and DES. Both BPA and DES (10-50μM) caused a significant activation of the CYP3A4 promoter via the PXR in the DPX2 human hepatoma cell line. No activation of rat PXR was seen. BPA and DES treated DPX2 cells demonstrated increased expression of CYP3A4 mRNA, and increased enzyme activity. In summary, BPA, in concentrations relevant to current safety levels of human exposure, activates the human PXR and demonstrates an increase in CYP3A4 mRNA expression and enzyme activity. BPA actions in this model system occur to a greater extent than DES. This study raises concerns regarding our current toxicity testing paradigms and species utilization.
authors: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Utah, 30 North 1900 East, Suite 2B200, Salt Lake City, UT 84112, United States. oumar.kuzbari@hsc.utah.edu
authors: Oumar
authors: O
authors: Kuzbari
authors: C Matthew
authors: CM
authors: Peterson
authors: Michael R
authors: MR
authors: Franklin
authors: Laura B
authors: LB
authors: Hathaway
authors: Erica B
authors: EB
authors: Johnstone
authors: Ahmad O
authors: AO
authors: Hammoud
authors: John G
authors: JG
authors: Lamb
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004054:Diethylstilbestrol / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D000077297:Pregnane X Receptor; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism; D018675:Toxicity Tests; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004054:Diethylstilbestrol; D052244:Endocrine Disruptors; D010636:Phenols; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C465260:Cyp3a2 protein, rat; C510163:CYP3A4 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds