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Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor SXR/PXR-mediated transcription
European Journal of Endocrinology v.145, i.4 Oct01

Akira Takeshita, Noriyuki Koibuchi1, Junko Oka, Manabu Taguchi, Yoshimasa Shishiba and Yasunori Ozawa

Division of Endocrinology and Metabolism, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo 105-8470 and 1Department of Physiology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan

(Correspondence should be addressed to Akira Takeshita, Division of Endocrinology and Metabolism, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan)

Abstract

Objective:
There is an increasing concern over endocrine disrupting chemicals (EDCs) that may produce adverse health effects in humans and other species. One of such chemicals, Bisphenol-A (BPA), a monomer of polycarbonate plastics, is widely used in consumer products. BPA has been reported to contain estrogenic activity through the binding to estrogen receptors. The cytochrome P450 monooxygenase 3A4 (CYP3A4) is one of the key enzymes for metabolism of endogenous steroids and foreign chemicals in liver. Recently, the orphan nuclear receptor, steroid and xenobiotic receptor (SXR/PXR), has 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 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 the species difference of SXR alters the CYP3A inducibilty.

Design:
We tested 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 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 indicate that BPA may be a human-specific inducer of CYP3A4 gene, and may influence the metabolism of endogenous steroids, drugs, and other xenobiotics.

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