PT  - JOURNAL ARTICLE
AU  - Jessica K. Rieger
AU  - Sandra Reutter
AU  - Ute Hofmann
AU  - Matthias Schwab
AU  - Ulrich M. Zanger
TI  - Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9
AID  - 10.1124/dmd.114.062844
DP  - 2015 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 884--888
VI  - 43
IP  - 6
4099  - http://dmd.aspetjournals.org/content/43/6/884.short
4100  - http://dmd.aspetjournals.org/content/43/6/884.full
SO  - Drug Metab Dispos2015 Jun 01; 43
AB  - Expression of genes involved in absorption, distribution, metabolism, and excretion (ADME) of drugs is impaired in pathophysiologic conditions such as cholestasis and inflammation. The mechanisms of ADME gene down-regulation remain unclear. In our previous study, strongly elevated levels of microRNAs (miRNA) miR-21, miR-34a, and miR-130b in cholestatic liver and of miR-21 and miR-130b during inflammation were observed. Using HepaRG cells, which retain many functional characteristics of human hepatocytes, we investigated the potential of these miRNAs to down-regulate ADME genes. Cells were transfected with the corresponding miRNA mimics, chemically modified double-stranded RNAs that mimic endogenous miRNAs, followed by mRNA profiling by quantitative reverse-transcription polymerase chain reaction. Activities of six cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4) were determined with a liquid chromatography with tandem mass spectrometric cocktail assay. Although miR-21 and miR-34a showed few effects, transfection of miR-130b led to significantly lower expression of nuclear receptors constitutive androstane receptor (CAR) and farnesoid X receptor (FXRα), the CYPs 1A1, 1A2, 2A6, 2C8, 2C9, and 2C19, as well as GSTA2. Furthermore, miR-130b negatively affected activity levels of all measured P450s by at least 30%. Reporter gene assays employing the CYP2C9 3′-untranslated region (3′-UTR) confirmed direct regulation by miR-130b. These data support miR-130b as a potential negative regulator of drug metabolism by directly and/or indirectly affecting the expression of several ADME genes. This may be of relevance in pathophysiologic conditions such as cholestasis and inflammation, which are associated with increased miR-130b expression.