Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription

• DOI: 10.1530/eje.0.1450513
• Publication Date: 2005-01-24T21:34:41Z
• Authors: A Takeshita; N Koibuchi; J Oka; M Taguchi; Y Shishiba; Y Ozawa
• Keywords: 0301 basic medicine; Receptors, Steroid; Transcription, Genetic; Pregnane X Receptor; Artificial Gene Fusion; Cell Line; Mixed Function Oxygenases; 3. Good health; 03 medical and health sciences; Nuclear Receptor Coactivator 1; Cytochrome P-450 Enzyme System; Phenols; Diethylhexyl Phthalate; Cytochrome P-450 CYP3A; Humans; Estrogens, Non-Steroidal; Benzhydryl Compounds; Histone Acetyltransferases; Transcription Factors

BACKGROUND: There is increasing concern about endocrine-disrupting chemicals (EDCs) which may produce adverse health effects in humans and other species. One such chemical, bisphenol-A (BPA), a monomer of polycarbonate plastics, is widely used in consumer products; it has been reported to contain estrogenic activity through binding to estrogen receptors. Cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is one of the key enzymes for the metabolism of endogenous steroids and foreign chemicals in liver. The orphan nuclear receptor, steroid and xenobiotic receptor (SXR/PXR), has recently been isolated. A variety of known inducers of CYP3A4 bind to SXR/PXR, and stimulate transcription on xenobiotic-response elements (XREs) located in the promoter region of the CYP3A4 gene. Recent study has shown that EDCs, diethylhexylphthalate (DEHP) and nonylphenol, but not BPA, induce mouse SXR/PXR-mediated transcription. However, it is known that species differences in SXR alter CYP3A inducibility. OBJECTIVE: To test whether BPA stimulates human SXR/PXR-mediated transcription using reporter gene assays. METHODS: Transfection assays were performed with human SXR/PXR expression plasmid and a reporter plasmid containing the XREs in the CYP3A4 gene promoter in HepG2 cells. BPA-induced interaction of human SXR/PXR with steroid receptor coactivator-1 (SRC-1) was analyzed by mammalian two-hybrid assays. RESULTS: BPA, as well as DEHP, activated human SXR-mediated transcription on the XREs. In mammalian two-hybrid assays, BPA recruited SRC-1 to the ligand-binding domain of human SXR/PXR. CONCLUSIONS: Our observations have indicated that BPA may be a human-specific inducer of the CYP3A4 gene, and may influence the metabolism of endogenous steroids, drugs, and other xenobiotics.