title: Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes.
abstract: Membrane drug transporters contribute to the disposition of many drugs. In human liver, drug transport is controlled by two main superfamilies of transporters, the solute carrier transporters (SLC) and the ATP Binding Cassette transporters (ABC). Altered expression of these transporters due to drug-drug interactions can contribute to differences in drug exposure and possibly effect. In this study, we determined the effect of rifampin on gene expression of hundreds of membrane transporters along with all clinically relevant drug transporters.
  
  
  METHODS
  In this study, primary human hepatocytes (n = 7 donors) were cultured and treated for 24 h with rifampin and vehicle control. RNA was isolated from the hepatocytes, mRNA expression was measured by RNA-seq, and miRNA expression was analyzed by Taqman OpenArray. The effect of rifampin on the expression of selected transporters was also tested in kidney cell lines. The impact of rifampin on the expression of 410 transporter genes from 19 different transporter gene families was compared with vehicle control.
  
  
  RESULTS
  Expression patterns of 12 clinically relevant drug transporter genes were changed by rifampin (FDR < 0.05). For example, the expressions of ABCC2, ABCB1, and ABCC3 were increased 1.9-, 1.7-, and 1.2-fold, respectively. The effects of rifampin on four uptake drug transporters (SLCO1B3, SLC47A1, SLC29A1, SLC22A9) were negatively correlated with the rifampin effects on specific microRNA expression (SLCO1B3/miR-92a, SLC47A1/miR-95, SLC29A1/miR-30d#, and SLC22A9/miR-20; r < -0.79; p < 0.05). Seven hepatic drug transporter genes (SLC22A1, SLC22A5, SLC15A1, SLC29A1, SLCO4C1, ABCC2, and ABCC4), whose expression was altered by rifampin in hepatocytes, were also present in a renal proximal tubular cell line, but in renal cells rifampin did not alter their gene expression. PXR expression was very low in the kidney cells; this may explain why rifampin induces gene expression in a tissue-specific manner.
  
  
  CONCLUSIONS
  Rifampin alters the expression of many of the clinically relevant hepatic drug transporters, which may provide a rational basis for understanding rifampin-induced drug-drug interactions reported in vivo. The relevance of its effect on many other transporters remains to be studied.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Benson
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Eadon
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Burgess
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Segar
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City and School of Medicine, University of Missouri-Kansas City Kansas City, MO, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
keywords: ChIP-Seq; PXR binding site; RNA sequencing; drug transporter; gene expression; human hepatocyte; microRNA; rifampin