J Appl Biomed 13:181-188, 2015 | DOI: 10.1016/j.jab.2015.04.002

Bioinformatic analysis of miRNAs targeting the key nuclear receptors regulating CYP3A4 gene expression: The challenge of the CYP3A4 "missing heritability" enigma

Tomas Smutny^a, Jurjen Duintjer Tebbens^b, Petr Pavek^a,*

^a Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove CZ-500 05, Czech Republic

^b Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove CZ-500 05, Czech Republic

The expression of the main cytochrome P450 enzyme CYP3A4 displays enormous interindividual variability. Studies addressing the genetic variability of either the CYP3A4 gene itself or its key transcription factors have not found any crucial polymorphism contributing to this variability in expression, a phenomenon is referred to as the "missing heritability of CYP3A4 variability." Several reports have recently described microRNAs (miRNAs) targeting the CYP3A4 gene and/or its major transcription factors.
A comprehensive bioinformatic analysis was performed using the miRDB, PITA, miRanda and TargetScan programs in the search for hypothetical miRNAs targeting 3'-untranslated regions of PXR, CAR, VDR, HNF4α, RXRα, SHP and GRα genes controlling CYP3A4 expression.
We propose several novel miRNAs identified parallelly by at least three algorithms to the target analyzed genes. In particular, we found novel promising miRNAs which may be involved in the indirect PXR-mediated CYP3A4 gene expression such as miR-18a and miR-18b, miR-449a, miR-449b and miR-34a. We also hypothesize that some miRNAs may play the role of a master regulator of NRs since they are predicted to target more than three genes.
The identification of miRNAs determining CYP3A4 interindividual variability might be an important step toward progress in pharmacogenetics and personalized medicine.

Keywords: miRNA; Gene regulation; CYP3A4; Cytochrome P450; Metabolism

Received: March 31, 2015; Accepted: April 9, 2015; Published: July 1, 2015  Show citation