Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription.
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.
Takeshita
A
A
Division of Endocrinology and Metabolism, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo 105-8470, Japan. coactivator@mac.com
Koibuchi
N
N
Oka
J
J
Taguchi
M
M
Shishiba
Y
Y
Ozawa
Y
Y
D019677:Artificial Gene Fusion; D001559:Benzhydryl Compounds; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D051548:Histone Acetyltransferases; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics; D056920:Nuclear Receptor Coactivator 1; D010636:Phenols / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; D004968:Estrogens, Non-Steroidal; D051548:Histone Acetyltransferases; D006899:Mixed Function Oxygenases; D056920:Nuclear Receptor Coactivator 1; D010636:Phenols; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014157:Transcription Factors; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds