title: [Involvement of microRNA in the induction of drug-metabolizing enzymes].
abstract: MicroRNAs (miRNAs) are small noncoding RNAs of about 20 nucleotides in length and participate in the post-transcriptional regulation of gene expression. Accumulating evidence indicates that miRNA binds to 3'-UTR of its target mRNAs and thereby destabilizes the transcripts or suppresses the translation. It is expected that miRNAs could have diverse functions and therefore play a role in the gene expression caused by the drug treatment, which have yet to be determined. Demonstration of the participation of specific miRNA in the drug-mediated gene expression would make it a biomarker for the toxicological assessment and help an understanding of molecular machinery of the drug-drug interaction. Under these backgrounds, we investigated the change of miRNAs in the liver of mice treated with phenobarbital, a typical inducer for drug-metabolizing enzymes, and demonstrate the participation of miRNAs in the phenobarbital-regulated gene expression. We investigated the relationship between phenobarbital-mediated changes in miRNA and mRNA by using Agilent miRNA microarray and DNA microarray, followed by real time RT-PCR. From these experiments, it was suggested that the phenobarbital-induced changes in cyp2c29 and mrp3 are regulated by miR-30a and miR-29b, respectively. In addition, we obtained evidence that indicates a phenobarbital-mediated decrease in miR-122, a highly abundant liver-specific miRNA, leads to the activation of the transcription factor CAR and thereby induces drug-metabolizing enzymes.
authors.affiliation: Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. r-shizu@pharm.showa-u.ac.jp
authors.forename: Ryota
authors.initials: R
authors.lastname: Shizu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Numazawa
authors.forename: Takemi
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions / Q000235:genetics; D004790:Enzyme Induction / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D043922:Toxicogenetics
chemical_list: D020413:3' Untranslated Regions; D000090702:Constitutive Androstane Receptor; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System; D055372:AMP-Activated Protein Kinases; D010634:Phenobarbital