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Molecular Pharmacology

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Research ArticleArticle

Negative Regulation of Human Pregnane X Receptor by MicroRNA-18a-5p: Evidence for Suppression of MicroRNA-18a-5p Expression by Rifampin and Rilpivirine

Devinder Sharma, Abdullah A. Turkistani, Wenjun Chang, Catherine Hu, Zhaoming Xu and Thomas K. H. Chang
Molecular Pharmacology July 2017, 92 (1) 48-56; DOI: https://doi.org/10.1124/mol.116.107003
Devinder Sharma
Faculty of Pharmaceutical Sciences, (D.S., A.A.T., C.H., T.K.H.C.), and Food, Nutrition, and Health Program, Faculty of Land and Food Systems (W.C., Z.X.), The University of British Columbia, Vancouver, British Columbia, Canada
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Abdullah A. Turkistani
Faculty of Pharmaceutical Sciences, (D.S., A.A.T., C.H., T.K.H.C.), and Food, Nutrition, and Health Program, Faculty of Land and Food Systems (W.C., Z.X.), The University of British Columbia, Vancouver, British Columbia, Canada
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Wenjun Chang
Faculty of Pharmaceutical Sciences, (D.S., A.A.T., C.H., T.K.H.C.), and Food, Nutrition, and Health Program, Faculty of Land and Food Systems (W.C., Z.X.), The University of British Columbia, Vancouver, British Columbia, Canada
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Catherine Hu
Faculty of Pharmaceutical Sciences, (D.S., A.A.T., C.H., T.K.H.C.), and Food, Nutrition, and Health Program, Faculty of Land and Food Systems (W.C., Z.X.), The University of British Columbia, Vancouver, British Columbia, Canada
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Zhaoming Xu
Faculty of Pharmaceutical Sciences, (D.S., A.A.T., C.H., T.K.H.C.), and Food, Nutrition, and Health Program, Faculty of Land and Food Systems (W.C., Z.X.), The University of British Columbia, Vancouver, British Columbia, Canada
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Thomas K. H. Chang
Faculty of Pharmaceutical Sciences, (D.S., A.A.T., C.H., T.K.H.C.), and Food, Nutrition, and Health Program, Faculty of Land and Food Systems (W.C., Z.X.), The University of British Columbia, Vancouver, British Columbia, Canada
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Abstract

Small noncoding microRNAs act as post-transcriptional regulators of gene expression involved in diverse biologic functions. Pregnane X receptor (PXR, NR1I2), a member of the superfamily of nuclear receptors, is a transcription factor governing the transport and biotransformation of various drugs and other chemicals. In the present study, we identified a specific microRNA (miR) involved in regulating the expression and functionality of human PXR (hPXR). According to bioinformatics analysis employing three commonly used algorithms (TargetScan, miRanda, and DIANA-microT-CDS), miR-18a-5p was predicted to be the top candidate microRNA regulator of hPXR. Consequently, this microRNA was selected for detailed experimental investigation. As shown in cell-based dual-luciferase reporter gene assays, functional interaction occurred between miR-18a-5p and the microRNA recognition element of miR-18a-5p in the 3′-untranslated region of hPXR mRNA. Transfection of LS180 human colorectal adenocarcinoma cells with an miR-18a-5p mimic decreased hPXR mRNA and protein expression, whereas transfection of LS180 cells with an miR-18a-5p inhibitor increased hPXR mRNA and protein expression. The decrease in hPXR expression by the miR-18a-5p mimic was associated with a reduction in the extent of hPXR target gene (CYP3A4) induction by rifampin and rilpivirine. Treatment of untransfected LS180 cells with either of these hPXR agonists decreased endogenous expression of miR-18a-5p, and this preceded the onset of CYP3A4 induction. In conclusion, miR-18a-5p is a negative regulator of hPXR expression and the hPXR agonists rifampin and rilpivirine are chemical suppressors of miR-18a-5p expression.

Footnotes

    • Received September 19, 2016.
    • Accepted April 4, 2017.
  • This research was supported by the Natural Sciences and Engineering Research Council of Canada [Grant 2014-03734]. A.A.T. received a King Saud Scholarship, Ministry of Higher Education, Saudi Arabia.

  • https://doi.org/10.1124/mol.116.107003.

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

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 92 (1)
Molecular Pharmacology
Vol. 92, Issue 1
1 Jul 2017
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Research ArticleArticle

MicroRNA-18a-5p and Pregnane X Receptor

Devinder Sharma, Abdullah A. Turkistani, Wenjun Chang, Catherine Hu, Zhaoming Xu and Thomas K. H. Chang
Molecular Pharmacology July 1, 2017, 92 (1) 48-56; DOI: https://doi.org/10.1124/mol.116.107003

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Research ArticleArticle

MicroRNA-18a-5p and Pregnane X Receptor

Devinder Sharma, Abdullah A. Turkistani, Wenjun Chang, Catherine Hu, Zhaoming Xu and Thomas K. H. Chang
Molecular Pharmacology July 1, 2017, 92 (1) 48-56; DOI: https://doi.org/10.1124/mol.116.107003
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