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Molecular Pharmacology

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Research ArticleArticle

MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

Kenji Ikemura, Misato Yamamoto, Saori Miyazaki, Hideki Mizutani, Takuya Iwamoto and Masahiro Okuda
Molecular Pharmacology February 2013, 83 (2) 399-405; DOI: https://doi.org/10.1124/mol.112.081844
Kenji Ikemura
College of Pharmacy, Kinjo Gakuin University (K.I., S.M., H.M.), Nagoya, Aichi, Japan; Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie, Japan (T.I., M.O.); and Department of Pharmacy, Mie University Hospital (M.Y., T.I., M.O.), Tsu, Mie, Japan
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Misato Yamamoto
College of Pharmacy, Kinjo Gakuin University (K.I., S.M., H.M.), Nagoya, Aichi, Japan; Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie, Japan (T.I., M.O.); and Department of Pharmacy, Mie University Hospital (M.Y., T.I., M.O.), Tsu, Mie, Japan
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Saori Miyazaki
College of Pharmacy, Kinjo Gakuin University (K.I., S.M., H.M.), Nagoya, Aichi, Japan; Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie, Japan (T.I., M.O.); and Department of Pharmacy, Mie University Hospital (M.Y., T.I., M.O.), Tsu, Mie, Japan
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Hideki Mizutani
College of Pharmacy, Kinjo Gakuin University (K.I., S.M., H.M.), Nagoya, Aichi, Japan; Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie, Japan (T.I., M.O.); and Department of Pharmacy, Mie University Hospital (M.Y., T.I., M.O.), Tsu, Mie, Japan
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Takuya Iwamoto
College of Pharmacy, Kinjo Gakuin University (K.I., S.M., H.M.), Nagoya, Aichi, Japan; Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie, Japan (T.I., M.O.); and Department of Pharmacy, Mie University Hospital (M.Y., T.I., M.O.), Tsu, Mie, Japan
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Masahiro Okuda
College of Pharmacy, Kinjo Gakuin University (K.I., S.M., H.M.), Nagoya, Aichi, Japan; Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie, Japan (T.I., M.O.); and Department of Pharmacy, Mie University Hospital (M.Y., T.I., M.O.), Tsu, Mie, Japan
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Abstract

P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemia-reperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the post-transcriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 3′-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 3′-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 3′-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 3′-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.

Footnotes

  • This work was supported by a Grant-in-Aid for Scientific Research (C) [23590180] and a Grant-in-Aid for Young Scientists (B) [23790206] from the Japan Society for the Promotion of Science.

  • dx.doi.org/10.1124.mol.112.081844.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received August 12, 2012.
  • Accepted November 19, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (2)
Molecular Pharmacology
Vol. 83, Issue 2
1 Feb 2013
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Research ArticleArticle

Post-transcriptional Regulation of P-glycoprotein by miR-145

Kenji Ikemura, Misato Yamamoto, Saori Miyazaki, Hideki Mizutani, Takuya Iwamoto and Masahiro Okuda
Molecular Pharmacology February 1, 2013, 83 (2) 399-405; DOI: https://doi.org/10.1124/mol.112.081844

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Research ArticleArticle

Post-transcriptional Regulation of P-glycoprotein by miR-145

Kenji Ikemura, Misato Yamamoto, Saori Miyazaki, Hideki Mizutani, Takuya Iwamoto and Masahiro Okuda
Molecular Pharmacology February 1, 2013, 83 (2) 399-405; DOI: https://doi.org/10.1124/mol.112.081844
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