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MicroRNA changes associated with atypical CYP1A1 inducer BMS-764459
Damir Simic1, Cathy Euler, Emily Haines
1Drug Safety Evaluation, Bristol-Myers Squibb, Mt. Vernon, IN 47620, USA. damir.simic@bms.com
Toxicology
|July 9, 2013
Summary
The drug BMS-764459, a corticotrophin releasing factor (CRF) receptor I antagonist, caused liver weight increases in rats by inducing specific genes. MicroRNA analysis identified miR-680 and miR-29a as key regulators and biomarkers of this effect.
Area of Science:
- Pharmacology and Toxicology
- Genomics and Molecular Biology
- Drug Metabolism
Background:
- BMS-764459, a corticotrophin releasing factor (CRF) receptor I antagonist, is investigated for affective disorder treatment.
- Drug-induced liver weight increases necessitate understanding underlying molecular mechanisms.
- Atypical induction of CYP1A1-like gene expression patterns suggests specific molecular pathways.
Purpose of the Study:
- To elucidate the mechanism behind BMS-764459-induced liver weight increases in rats.
- To identify gene and microRNA expression changes associated with BMS-764459 administration.
- To determine the role of microRNAs in the drug's effect on xenobiotic-metabolizing enzymes.
Main Methods:
- Oral administration of BMS-764459 to Sprague-Dawley rats for 2 weeks.
- Microarray analysis of liver mRNA from snap-frozen tissue to assess gene expression.
- RT-PCR analysis of mRNA and microRNA (miRNA) from Formalin Fixed Paraffin Embedded (FFPE) samples.
- In silico evaluation of differentially expressed miRNAs and their predicted mRNA targets.
Main Results:
- BMS-764459 induced AhR target genes, CYP2B, CYP3A, and Abcc3, consistent with atypical CYP1A1 inducer patterns.
- Significant alterations in miRNA expression were observed.
- MiR-680 and miR-29a were identified as potential regulators and biomarkers of atypical CYP1A1 induction.
- These miRNAs were predicted to regulate Abcc3, CYP3A, CYP2B, and other AhR target genes.
Conclusions:
- BMS-764459 exhibits an atypical CYP1A1 induction profile, impacting xenobiotic metabolism pathways.
- Specific miRNAs, notably miR-680 and miR-29a, play a regulatory role in this induction.
- These miRNAs may serve as biomarkers for atypical CYP1A1 induction by CRF receptor antagonists.
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