title: RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence.
abstract: Adenosine to inosine (A-to-I) RNA editing is the most frequent type of post-transcriptional nucleotide conversion in humans, and it is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. In this study we investigated the effect of RNA editing on human aryl hydrocarbon receptor (AhR) expression because the AhR transcript potentially forms double-stranded structures, which are targets of ADAR enzymes. In human hepatocellular carcinoma-derived Huh-7 cells, the ADAR1 knockdown reduced the RNA editing levels in the 3'-untranslated region (3'-UTR) of the AhR transcript and increased the AhR protein levels. The ADAR1 knockdown enhanced the ligand-mediated induction of CYP1A1, a gene downstream of AhR. We investigated the possibility that A-to-I RNA editing creates miRNA targeting sites in the AhR mRNA and found that the miR-378-dependent down-regulation of AhR was abolished by ADAR1 knockdown. These results indicated that the ADAR1-mediated down-regulation of AhR could be attributed to the creation of a miR-378 recognition site in the AhR 3'-UTR. The interindividual differences in the RNA editing levels within the AhR 3'-UTR in a panel of 32 human liver samples were relatively small, whereas the differences in ADAR1 expression were large (220-fold). In the human liver samples a significant inverse association was observed between the miR-378 and AhR protein levels, suggesting that the RNA-editing-dependent down-regulation of AhR by miR-378 contributes to the variability in the constitutive hepatic expression of AhR. In conclusion, this study uncovered for the first time that A-to-I RNA editing modulates the potency of xenobiotic metabolism in the human liver.
authors.affiliation: From the Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakano
authors.affiliation: From the Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.affiliation: From the Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and.
authors.forename: Saki
authors.initials: S
authors.lastname: Gotoh
authors.affiliation: Department of Legal Medicine, Iwate Medical University School of Medicine, Uchimaru, Morioka 020-8505, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Takamiya
authors.affiliation: Department of Legal Medicine, Iwate Medical University School of Medicine, Uchimaru, Morioka 020-8505, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: From the Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan and nmiki@p.kanazawa-u.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000243:Adenosine Deaminase / Q000378:metabolism; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008099:Liver / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D017393:RNA Editing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D020413:3' Untranslated Regions; D000243:Adenosine Deaminase; D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C526012:MIRN378 microRNA, human; C000595356:ADAR protein, human; C567955:ADARB1 protein, human
keywords: RNA editing; aryl hydrocarbon receptor (AhR) (AHR); cytochrome P450; drug metabolism; microRNA (miRNA)