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

Background: There is increasing concern about endocrine-disrupting chemical s (EDCs) which may produce adverse health effects in humans and other speci es. One such chemical, bisphenol-A (BPA), a monomer of polycarbonate plasti cs, is widely used in consumer products; it has been reported to contain es trogenic activity through binding to estrogen receptors. Cytochrome P450 mo nooxygenase 3A4 (CYP3A4) is one of the key enzymes for the metabolism of en dogenous steroids and foreign chemicals in liver. The orphan nuclear recept or. steroid and xenobiotic receptor (SXR/PXR). has recently been isolated. A variety of known inducers of CYP3A4 bind to SXR/PXR, and stimulate transc ription on xenobiotic-response elements (XREs) located in the promoter regi on of the CYP3A4 gene. Recent study has shown that EDCs, diethylhexylphthal ate (DEHP) and nonylphenol, but not BPA, induce mouse SXR/PXR-mediated tran scription. However, it is known that species differences in SXR alter CYP3A inducibility. Objective: To test whether BPA stimulates human SXR/PXR-mediated transcript ion using reporter gene assays. Methods: Transfection assays were performed with human SXR/PXR expression p lasmid and a reporter plasmid containing the XREs in the CYP3A4 gene promot er in HepG2 cells. BPA-induced interaction of human SXR/PXR with steroid re ceptor coactivator-1 (SRC-1) was analyzed by mammalian two-hybrid assays. Results: BPA, as well as DEHP, activated human SXR-mediated transcription o n the XREs. In mammalian two-hybrid assays, BPA recruited SRC-1 to the liga nd-binding domain of human SXR/PXR. Conclusions: Our observations have indicated that BPA may be a human-specif ic inducer of the CYP3A4 gene, and may influence the metabolism of endogeno us steroids, drugs, and other xenobiotics.