DMD052886 1763..1768

Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (miRNAs) have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin, and the expression of miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 genes (P < 0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (P < 0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin-treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes, and some of the changes were correlated with the rifampin-induced changes in expression of the P450 mRNAs they are predicted to target.

[1]  Zhongyan Wang,et al.  The role of microRNAs in hepatocyte nuclear factor-4alpha expression and transactivation. , 2013, Biochimica et Biophysica Acta.

[2]  M. Gazouli,et al.  Expression of microRNAs, miR‐21, miR‐31, miR‐122, miR‐145, miR‐146a, miR‐200c, miR‐221, miR‐222, and miR‐223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance , 2013, Molecular carcinogenesis.

[3]  Yang Wang,et al.  No Correlation of hsa-miR-148a with Expression of PXR or CYP3A4 in Human Livers from Chinese Han Population , 2013, PloS one.

[4]  Y. Liu,et al.  Analysis of differentially expressed genes and microRNAs in alcoholic liver disease. , 2013, International journal of molecular medicine.

[5]  E. Androphy,et al.  COPI transport complexes bind to specific RNAs in neuronal cells. , 2013, Human molecular genetics.

[6]  Yunlong Liu,et al.  NGSUtils: a software suite for analyzing and manipulating next-generation sequencing datasets , 2013, Bioinform..

[7]  Guohua Wang,et al.  Potential roles of microRNAs in regulating long intergenic noncoding RNAs , 2013, BMC Medical Genomics.

[8]  Yiliang Zhang,et al.  Hepatitis C virus‐induced up‐regulation of microRNA‐155 promotes hepatocarcinogenesis by activating Wnt signaling , 2012, Hepatology.

[9]  T. Fukami,et al.  Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24. , 2012, Toxicology and applied pharmacology.

[10]  T. Skaar,et al.  In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes. , 2011, Drug metabolism letters.

[11]  T. Luedde,et al.  Micro‐RNA profiling reveals a role for miR‐29 in human and murine liver fibrosis , 2011, Hepatology.

[12]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[13]  Shingo Takagi,et al.  MicroRNAs Regulate Human Hepatocyte Nuclear Factor 4α, Modulating the Expression of Metabolic Enzymes and Cell Cycle* , 2009, The Journal of Biological Chemistry.

[14]  S. Nelson,et al.  BFAST: An Alignment Tool for Large Scale Genome Resequencing , 2009, PloS one.

[15]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[16]  Shingo Takagi,et al.  Post-transcriptional Regulation of Human Pregnane X Receptor by Micro-RNA Affects the Expression of Cytochrome P450 3A4* , 2008, Journal of Biological Chemistry.

[17]  T. Self,et al.  Update on Rifampin and Rifabutin Drug Interactions , 2003, The American journal of the medical sciences.

[18]  Shingo Takagi,et al.  MicroRNA regulates the expression of human cytochrome P450 1B1. , 2006, Cancer research.

[19]  Jiezhong Chen,et al.  Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. , 2006 .

[20]  H. Remmer,et al.  Determination of drug metabolizing enzymes in needle biopsies of human liver , 1972, European Journal of Clinical Pharmacology.

[21]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[22]  Timothy M Willson,et al.  The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. , 2002, Endocrine reviews.

[23]  Michael D. Johnson,et al.  Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. , 2001, The Journal of pharmacology and experimental therapeutics.

[24]  R Ohlsson,et al.  Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Lehmann,et al.  The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. , 1998, The Journal of clinical investigation.

[26]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[27]  M. Holdiness.  Rifampin drug interactions. , 1987, Archives of internal medicine.