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タイトル: Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4.
著者: Takagi, Shingo
Nakajima, Miki link image link image
Mohri, Takuya
Yokoi, Tsuyoshi link image
中嶋, 美紀
横井, 毅
発行日: 2008年 4月11日
出版社(者): American Society for Biochemistry and Molecular Biology
雑誌名: The Journal of biological chemistry
ISSN: 0021-9258
巻: 283
号: 15
開始ページ: 9674
終了ページ: 9680
抄録: Pregnane X receptor (PXR) is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes, including CYP3A4 (cytochrome P450 3A4). We first found that the PXR mRNA level was not correlated with the PXR protein level in a panel of 25 human livers, indicating the involvement of post-transcriptional regulation. Notably, a potential miR-148a recognition element was identified in the 3'-untranslated region of human PXR mRNA. We investigated whether PXR might be regulated by miR-148a. A reporter assay revealed that miR-148a could recognize the miR-148a recognition element of PXR mRNA. The PXR protein level was decreased by the overexpression of miR-148a, whereas it was increased by inhibition of miR-148a. The miR-148a-dependent decrease of PXR protein attenuated the induction CYP3A4 mRNA. Furthermore, the translational efficiency of PXR (PXR protein/PXR mRNA ratio) was inversely correlated with the expression levels of miR-148a in a panel of 25 human livers, supporting the miR-148a-dependent regulation of PXR in human livers. Eventually, the PXR protein level was significantly correlated with the CYP3A4 mRNA and protein levels. In conclusion, we found that miR-148a post-transcriptionally regulated human PXR, resulting in the modulation of the inducible and/or constitutive levels of CYP3A4 in human liver. This study will provide new insight into the unsolved mechanism of the large interindividual variability of CYP3A4 expression.
DOI: 10.1074/jbc.M709382200
URI: http://hdl.handle.net/2297/10013
資料種別: Journal Article
版表示: author
出現コレクション:2.査読済論文(薬)

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