Abstract

Rifampin causes drug interactions by altering hepatic drug metabolism. Since miRNAs have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin and the expression of miRNAs and CYP mRNAs were measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional CYP genes and repressed the expression of 9 other CYP genes (p<0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (p<0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target CYP mRNAs, supporting the possibility of miRNA-induced regulation of CYP mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in CYP mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin- treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes and some of the changes were correlated with the rifampin-induced changes in expression of the CYP mRNAs they are predicted to target.