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. Epub 2015 Aug 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Transport
  • Gene Expression Regulation
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Heterozygote
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism*
  • Kinetics
  • Liver / metabolism*
  • Mutation, Missense
  • Organic Anion Transporters, Sodium-Independent / genetics*
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Pharmacogenomic Variants / genetics*
  • Phenotype
  • Pravastatin / metabolism*
  • Transfection
  • Whites / genetics

Substances

  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Organic Anion Transporters, Sodium-Independent
  • SLC22A9 protein, human
  • Pravastatin