Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors

  • Pharmacogenomics J. 2016 Aug;16(4):341-51. doi: 10.1038/tpj.2015.55.
A Emami Riedmaier  1  2 ,  O Burk  1  2 ,  B A C van Eijck  1  2 ,  E Schaeffeler  1  2 ,  K Klein  1  2 ,  S Fehr  3 ,  S Biskup  3 ,  S Müller  1  2 ,  S Winter  1  2 ,  U M Zanger  1  2 ,  M Schwab  1  2  4 ,  A T Nies  1  2
Affiliations
  • 1. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
  • 2. University of Tübingen, Tübingen, Germany.
  • 3. CeGaT GmbH, Tübingen, Germany.
  • 4. Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany.
PMID: 26239079 DOI: 10.1038/tpj.2015.55
Abstract

Human organic anion transporter 7 (OAT7, SLC22A9) is a hepatic transport protein poorly characterized so far. We therefore sought to identify novel OAT7 substrates and factors contributing to variable hepatic OAT7 expression. Using OAT7-expressing cells, pravastatin was identified as a substrate. Hepatic SLC22A9/OAT7 mRNA and protein expression varied 28-fold and 15-fold, respectively, in 126 Caucasian liver samples. Twenty-four variants in SLC22A9 were genotyped, including three rare missense variants (rs377211288, rs61742518, rs146027075), which occurred only heterozygously. No variant significantly affected hepatic SLC22A9/OAT7 expression. The three missense variants, however, showed functional consequences when expressed in vitro. Hepatic nuclear factor 4-alpha (HNF4α) emerged as a major transcriptional regulator of SLC22A9 by a series of in silico and in vitro analyses. In conclusion, pravastatin is the first identified OAT7 drug substrate. Substantial inter-individual variability in hepatic OAT7 expression, majorly driven by HNF4α, may contribute to pravastatin drug disposition and might affect response.The Pharmacogenomics Journal advance online publication, 4 August 2015; doi:10.1038/tpj.2015.55.