title: MicroRNA changes associated with atypical CYP1A1 inducer BMS-764459.
abstract: The corticotrophin releasing factor (CRF) receptor I antagonist, BMS-764459 (evaluated as a potential treatment of affective disorders), was orally dosed to female Sprague-Dawley rats once daily for 2 weeks (vehicle control or 175mg/kg/day). To investigate the mechanism of BMS-764459-related liver weight increases, total liver RNA was isolated and evaluated for mRNA gene expression by microarray analysis (assessing the expression of approximately 24,000 genes) from snap-frozen tissue. Subsequently, mRNA and miRNA (microRNA) were also analyzed 5 years later from FFPE (Formalin Fixed Paraffin Embedded) samples via RT-PCR (about 800 miRNA evaluated). Genomic analyses showed that BMS-764459 induces AhR target genes with additional inductions of CYP2B, CYP3A, and Abcc3 consistent with the gene expression pattern of atypical CYP1A1 inducers. Analysis of miRNA expression identified a number of significantly affected miRNAs. To further evaluate their role in atypical CYP1A1 induction, an in silico evaluation of differentially expressed miRNA was performed and their putative mRNA 3'-UTR (untranslated region) binding sequences were evaluated. MiR-680 and miR-29a were identified as potential regulators and biomarkers of atypical CYP1A1 induction by regulating Abcc3, CYP3A and CYP2B as well as a number of AhR targeted genes.
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, Mt. Vernon, IN 47620, USA. damir.simic@bms.com
authors.forename: Damir
authors.initials: D
authors.lastname: Simic
authors.forename: Cathy
authors.initials: C
authors.lastname: Euler
authors.forename: Emily
authors.initials: E
authors.lastname: Haines
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.forename: W Mike
authors.initials: WM
authors.lastname: Peden
authors.forename: R Todd
authors.initials: RT
authors.lastname: Bunch
authors.forename: Thomas
authors.initials: T
authors.lastname: Sanderson
authors.forename: Terry
authors.initials: T
authors.lastname: Van Vleet
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D005557:Formaldehyde / Q000494:pharmacology; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016612:Paraffin Embedding / Q000379:methods; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000631:Aminopyridines; C584056:BMS-764459; D035683:MicroRNAs; D011719:Pyrazines; D012333:RNA, Messenger; D005557:Formaldehyde; D019363:Cytochrome P-450 CYP1A1
keywords: AhR; CYP1A1; miRNA