title: Modulation of ALDH5A1 and SLC22A7 by microRNA hsa-miR-29a-3p in human liver cells.
abstract: Observed variations in drug responses among patients may result from differences in heritable genetic traits or from alterations in the epigenetic regulation of drug metabolizing enzymes and transporters (DMETs). MicroRNAs (miRNAs), a group of small non-coding RNAs, provide an epigenetic mechanism for fine-tuning the expression of targeted DMET genes by regulating the efficiency of protein translation and by decreasing mRNA stability via enhanced degradation. In the current study we systematically screened 374 important genes encoding DMETs for potential response elements to hsa-miR-29a-3p, a highly abundant miRNA in human liver. RNA electrophoresis mobility shift assays displayed direct interactions between hsa-miR-29a-3p and its cognate targets within the mRNA transcripts for the ABCC6, SLC22A7 and ALDH5A1 genes. The expression of luciferase reporter genes containing the 3'-UTRs of SLC22A7 or ALDH5A1 and the expression of endogenous SLC22A7 and ALDH5A1 were each suppressed by transfection with hsa-miR-29a-3p mimics. Importantly, chemically-induced up-regulation of hsa-miR-29a-3p correlated inversely with the expression of SLC22A7 and ALDH5A1. However, our studies failed to detect suppressive effects of hsa-miR-29a-3p on ABCC6 expression, which might be explained by the notion that the interaction of hsa-miR-29a-3p and ABCC6 mRNA was unable to recruit ribonucleoproteins to form a RNA-induced silencing complex.
authors.affiliation: National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Dianke
authors.initials: D
authors.lastname: Yu
authors.affiliation: National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Tolleson
authors.affiliation: National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Bridgett
authors.initials: B
authors.lastname: Knox
authors.affiliation: Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Jin
authors.affiliation: National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guo
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Kadlubar
authors.affiliation: National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: baitang.ning@fda.hhs.gov.
authors.forename: Baitang
authors.initials: B
authors.lastname: Ning
mesh_terms: D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000502:physiology*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase
keywords: ALDH5A1; Drug metabolizing enzymes and transporters; Pharmacogenomics; SLC22A7; hsa-miR-29a-3p; microRNA