PII-021

E. A. Benson,1 Z. Desta,1 Y. Liu,1 M. Eadon,1 A. Gaedigk,2 T. C. Skaar1; 1Indiana University School of Medicine, Indianapolis, IN, 2Children's Mercy Hospital, Kansas City, MO

BACKGROUND: Rifampin regulates the expression of many drug metabolism genes, but less is known about its effect on drug transporter genes. Rifampin regulates gene expression by activating the nuclear receptor pregnane X receptor (PXR); however, rifampin may also regulate gene expression indirectly by altering miRNA expression. The goal of this study was to investigate the coordinate rifampin regulation of drug transporter and miRNA gene expression in primary human hepatocytes.
METHODS: Human hepatocytes from seven donors grown on collagen coated plates and were treated with 10 uM of rifampin for 24 hours along with corresponding methanol vehicle control. RNA was isolated using miRNeasy kit (Qiagen, Valencia, CA). The mRNA expression was determined by RNA sequencing. The miRNA expression profile was measured by Taqman OpenArray Human miRNA Panel (Applied Biosystems, Foster City, CA).
RESULTS: Of the 410 transporters from 20 different transporter superfamilies studied, 107 were regulated by rifampin in the primary human hepatocytes. Of the 32 most clinically relevant drug transporters, 12 were regulated by rifampin; three of these known to be regulated by PXR. The expressions of 5 of the 12 genes were highly negatively correlated with specific miRNA expression.
CONCLUSION: Our studies demonstrated that rifampin regulates a large number of important drug transporters in human hepatocytes. Some of the rifampin effect is likely due to its activation of PXR, but its regulation of miRNAs may also be important. Thus, rifampin regulation of hepatic miRNAs may be an important mechanism of altered drug transporter expression and drug disposition.