Abstract
Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (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 miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 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 P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 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 P450 mRNAs they are predicted to target.
Footnotes
- Received May 10, 2013.
- Accepted August 9, 2013.
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant RO1-GM088076]; and the Department of Defense predoctoral fellowship [Grant BC083078].
Parts of this work were presented as follows: Ramamoorthy A, Flockhart DA, and Skaar TC (2010) Rifampin regulates hepatic miRNA expression. American Society for Clinical Pharmacology and Therapeutics Annual Meeting; 2010 Mar 17–20; Atlanta, GA; and Ramamoorthy A, Liu Y, Goswami C, Philips S, Gaedigk A, Flockhart DA, Desta Z, Skaar TC (2012) Global analysis of rifampin-regulated mRNA and miRNA gene expression in primary human hepatocytes. American Society for Clinical Pharmacology and Therapeutics Annual Meeting; 2012 Mar 12–17; National Harbor, MD.
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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