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MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

Yu-Zhuo Pan, Wenqing Gao and Ai-Ming Yu
Drug Metabolism and Disposition October 2009, 37 (10) 2112-2117; DOI: https://doi.org/10.1124/dmd.109.027680
Yu-Zhuo Pan
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Wenqing Gao
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Ai-Ming Yu
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Abstract

CYP3A4 metabolizes many drugs on the market. Although transcriptional regulation of CYP3A4 is known to be tightly controlled by some nuclear receptors (NR) including vitamin D receptor (VDR/NR1I1), posttranscriptional regulation of CYP3A4 remains elusive. In this study, we show that noncoding microRNAs (miRNAs) may control posttranscriptional and transcriptional regulation of CYP3A4 by directly targeting the 3′-untranslated region (3′UTR) of CYP3A4 and indirectly targeting the 3′UTR of VDR, respectively. Luciferase reporter assays showed that CYP3A4 3′UTR-luciferase activity was significantly decreased in human embryonic kidney 293 cells transfected with plasmid that expressed microRNA-27b (miR-27b) or mouse microRNA-298 (mmu-miR-298), whereas the activity was unchanged in cells transfected with plasmid that expressed microRNA-122a or microRNA-328. Disruption of the corresponding miRNA response element (MRE) within CYP3A4 3′UTR led to a 2- to 3-fold increase in luciferase activity. Immunoblot analyses indicated that CYP3A4 protein was down-regulated over 30% by miR-27b and mmu-miR-298 in LS-180 and PANC1 cells. The decrease in CYP3A4 protein expression was associated with significantly decreased CYP3A4 mRNA levels, as determined by quantitative real-time PCR (qPCR) analyses. Likewise, interactions of miR-27b or mmu-miR-298 with VDR 3′UTR were supported by luciferase reporter assays. The mmu-miR-298 MRE site is well conserved within the 3′UTR of mouse, rat, and human VDR. Down-regulation of VDR by the two miRNAs was supported by immunoblot and qPCR analyses. Furthermore, overexpression of miR-27b or mmu-miR-298 in PANC1 cells led to a lower sensitivity to cyclophosphamide. Together, these findings suggest that CYP3A4 gene expression may be regulated by miRNAs at both the transcriptional and posttranscriptional level.

  • PXR, pregnane X receptor
  • VDR, vitamin D receptor
  • RXRα, retinoid X receptor alpha
  • 3′UTR, 3′-untranslated region
  • miRNA, microRNA
  • miR-148a, microRNA-148a
  • miR-27b, microRNA-27b
  • mu-miR-298, mouse microRNA-298
  • MRE, miRNA response element
  • VD3, 1α-hydroxycholecalciferol
  • DMEM, Dulbecco's modified Eagle's medium
  • FBS, fetal bovine serum
  • HEK, human embryonic kidney
  • GAPDH, glyceraldehyde 3-phosphate dehydrogenase
  • bp, base pair
  • PAGE, polyacrylamide gel
  • qPCR, quantitative real-time polymerase chain reaction
  • CDS, coding sequence
  • ANOVA, analysis of variance
  • Tg, transgenic.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA021172]; and the Interdisciplinary Research Development Fund, University at Buffalo, SUNY.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received March 23, 2009.
    • Accepted June 30, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (10)
Drug Metabolism and Disposition
Vol. 37, Issue 10
October 2009
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OtherAccelerated Communication

MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

Yu-Zhuo Pan, Wenqing Gao and Ai-Ming Yu
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2112-2117; DOI: https://doi.org/10.1124/dmd.109.027680

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MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

Yu-Zhuo Pan, Wenqing Gao and Ai-Ming Yu
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2112-2117; DOI: https://doi.org/10.1124/dmd.109.027680
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