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Biochem Pharmacol. 2015 Nov 1;98(1):215-23. doi: 10.1016/j.bcp.2015.08.094. Epub 2015 Aug 19.

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells.

Author information

1
National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
2
Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
3
Arkansas Department of Health, Little Rock, AR 72205, USA.
4
National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: baitang.ning@fda.hhs.gov.

Abstract

Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of -27.5kcal/mol and -23.3kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsa-miR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression.

KEYWORDS:

CYP2C19; Drug metabolizing enzymes; Inter-individual variability; Pharmacogenomics; hsa-miR-29a-3p; microRNA

PMID:
26296572
PMCID:
PMC5673105
DOI:
10.1016/j.bcp.2015.08.094
[Indexed for MEDLINE]
Free PMC Article

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