| Co-Investigator(Kenkyū-buntansha) |
MIZUTANI Yasushi Okayama University, Hospital, Assistant, 医学部・附属病院, 助手 (20294465)
HIRAMATSU Yuji Okayama Univereity, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (80218817)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Recently, Pregnane X receptor (PXR), a new member of the nuclear receptor superfamily, was shown to mediate the effects of several steroid hormones and xenobiotics on cytochrome P450 3A genes (CYP3A), suggesting that PXR may play a role in steroid hormone metabolism. Here, we demonstrated that phthalic acid and nonylphenol, endocrine disrupting chemicals (EDCs), stimulated PXR- mediated transcription and that PXR interacted with two nuclear receptor coactivator proteins, steroid hormone receptor coactivator-1 and receptor interacting protein 140, in the presence of phthalic acid or nonylphenol. The expression of PXR mRNA was observed in the liver, intestine, uterus, ovary and placenta. The expressions in the liver and ovary increased toward term about fifty-fold compared to that of non-pregnancy and decreased postpartum. Its expression in the placenta was not drastically changed toward term. CYP3A was also expressed in the liver, ovary, and placenta. The expressions of CYP3A mRNA as well as PXR in the liver and ovary increased about twenty-fold during prenatal period. Finally, we demonstrated that pregnane X receptor (PXR) interacted with suppressor for gall (SUGI), a component of the 26S proteasome, in a progesterone-dependent manner, but that phthalic acid and nonylphehol, which activated PXR-mediated transcription, did not enhance this interaction. Moreover, these EDC blocked the PXR degradation by proteasome.
These data suggest that EDCs may affect endocrine functions by altering steroid hormone metabolism through PXR and that EDCs may also affect PXR-mediated transcription of target genes through the upregulation of PXR protein level. And PXR may play certain roles in perinatal period, possibly in the protection of the feto-maternal system from the toxic effect of endogenous steroids and foreign substrates.
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