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 monooxygenase 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-speci®c inducer of the CYP3A4 gene, and may in¯uence the metabolism of endogenous steroids, drugs, and other xenobiotics.

Insulin gene expression is regulated by pancreatic ␤ cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-␤ cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/ E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/E47. This synergistic activation by SREBP-1c/BETA2/E47 was not mediated through SREs but through the E-boxes on which BETA2/E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c⅐BETA2⅐E47 complex in a DNA looping structure for efficient recruitment of CREB-binding protein/ p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in ␤ cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with ␤ cell lipotoxicity.

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Both HFJV and CPAP can improve oxygenation during OLV.

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