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Microrna-145 Post-Transcriptionally Regulates the Expression and Function of P-Glycoprotein In Intestinal Epithelial Cells.


Mol Pharmacol. 2012 Nov 19;


Authors: Ikemura K, Yamamoto M, Miyazaki S, Mizutani H, Iwamoto T, Okuda M


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 down-regulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 3'f-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 3'f-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'f-UTR abolished this decreased luciferase activity. The down-regulation 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'f-UTR of MDR1 mRNA. In addition, the down-regulation 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.

PMID: 23166305 [PubMed - as supplied by publisher]