Genome-wide microRNA profiles identify miR-107 as a top miRNA associating with expression of the CYP3As and other drug metabolizing cytochrome P450 enzymes in the liver

Abstract

Cytochrome P450 (CYP) drug metabolizing enzymes are responsible for the metabolism of over 70% of currently used medications with the CYP3A family being the most important CYP enzymes in the liver. Large inter-person variability in expression/activity of the CYP3As greatly affects drug exposure and treatment outcomes, yet the cause of such variability remains elusive. Micro-RNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression and are involved in diverse cellular processes including metabolism of xenobiotics and therapeutic outcomes. Target prediction and in vitro functional assays have linked several miRNAs to the control of CYP3A4 expression. Yet, their co-expression with CYP3As in the liver remain unclear. In this study, we used genome-wide miRNA profiling in liver samples to identify miRNAs associated with the expression of the CYP3As. We identified and validated both miR-107 and miR-1260 as strongly associated with the expression of CYP3A4, CYP3A5, and CYP3A43. Moreover, we found associations between miR-107 and nine transcription factors (TFs) that regulate CYP3A expression, with estrogen receptor alpha (ESR1) having the largest effect size. Including ESR1 and the other TFs in the regression model either diminished or abolished the associations between miR-107 and the CYP3As, indicating that the role of miR-107 in CYP3A expression may be indirect and occur through these key TFs. Indeed, testing the other nine CYPs previously shown to be regulated by ESR1 identified similar miR-107 associations that were dependent on the exclusion of ESR1 and other key TFs in the regression model. In addition, we found significant differences in miRNA expression profiles in liver samples between race and sex. Together, our results identify miR-107 as a potential epigenetic regulator that is strongly associated with the expression of many CYPs, likely via impacting the CYP regulatory network controlled by ESR1 and other key TFs. Therefore, both genetic and epigenetic factors that alter the expression of miR-107 may have a broad influence on drug metabolism.