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Research ArticleSpecial Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters

Expression Variability of Absorption, Distribution, Metabolism, Excretion–Related MicroRNAs in Human Liver: Influence of Nongenetic Factors and Association with Gene Expression

Jessica K. Rieger, Kathrin Klein, Stefan Winter and Ulrich M. Zanger
Drug Metabolism and Disposition October 2013, 41 (10) 1752-1762; DOI: https://doi.org/10.1124/dmd.113.052126
Jessica K. Rieger
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and University of Tuebingen, Tuebingen, Germany
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Kathrin Klein
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and University of Tuebingen, Tuebingen, Germany
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Stefan Winter
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and University of Tuebingen, Tuebingen, Germany
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Ulrich M. Zanger
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and University of Tuebingen, Tuebingen, Germany
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Abstract

Genes that are important for the detoxification of drugs and other xenobiotics show a high degree of interindividual variation attributable to regulation by diverse genetic, nongenetic, and epigenetic mechanisms including microRNAs (miRNAs). We selected a set of 56 miRNAs predicted to target the 3′-untranslated region of absorption, distribution, metabolism, excretion (ADME) genes to assess their hepatic expression levels and interindividual variability in a well-documented human liver tissue cohort (n = 92), together with the well-known hepatic miRNAs miR-122, miR-21, miR-27b, and miR-148a. Quantification by stem-loop real-time reverse-transcription polymerase chain reaction confirmed high expression for these microRNAs and revealed particularly strong variability of expression (>1000-fold) for miR-539, miR-200c, miR-31, miR-15a, and miR-22. Association analysis revealed a high degree of correlation among various miRNAs, suggesting coregulation. Statistical analysis considering liver donor meta-data including correction for multiple testing revealed strongly elevated levels of miR-21, miR-34a, miR-130b, and miR-132 in cholestatic liver and of miR-21 and miR-130b during inflammation, as indicated by elevated C-reactive protein levels in serum. Although none of the miRNAs was strongly associated with sex, several miRNAs, including miR-34a and miR-200a/b, were positively correlated with age. Association analysis with ADME gene expression profiles and with cytochrome P450 gene expression phenotypes (mRNA, protein, enzymatic activity) revealed numerous significant correlations. Negatively affected protein and/or activity levels were observed for CYP1A1 (e.g., miR-132, miR-142-3p, miR-21), CYP2A6 (miR-142-3p, miR-21), CYP2C19 (e.g., miR-130b, miR-185, miR-34a), and CYP2E1 (miR-10a, let-7g, miR-200c). These data should be useful to further elucidate regulatory functions of miRNAs in liver pathophysiology and regulation of ADME gene expression.

Footnotes

    • Received January 19, 2013.
    • Accepted March 12, 2013.
  • This study was supported by the German Federal Ministry of Education and Research Virtual Liver Network [Grant 0315755]; and by the Robert Bosch Foundation, Stuttgart, Germany.

  • dx.doi.org/10.1124/dmd.113.052126.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (10)
Drug Metabolism and Disposition
Vol. 41, Issue 10
1 Oct 2013
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Research ArticleSpecial Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters

MicroRNAs and Cytochromes in Human Liver

Jessica K. Rieger, Kathrin Klein, Stefan Winter and Ulrich M. Zanger
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1752-1762; DOI: https://doi.org/10.1124/dmd.113.052126

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Research ArticleSpecial Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters

MicroRNAs and Cytochromes in Human Liver

Jessica K. Rieger, Kathrin Klein, Stefan Winter and Ulrich M. Zanger
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1752-1762; DOI: https://doi.org/10.1124/dmd.113.052126
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