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

• Bioinformatic analysis of miRNAs targeting the nuclear receptors regulating CYP3A4 gene.
• Novel miRNAs identified by at least three algorithms for PXR, VDR, and RXRα genes controlling CYP3A4.
• Novel miRNAs involved in the indirect PXR-mediated CYP3A4 gene expression.
• Some miRNAs may play the role of a master regulator of NRs regulating more than three genes.

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.

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