title: Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors.
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.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Emami Riedmaier
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Burk
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: B A C
authors.initials: BA
authors.lastname: van Eijck
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schaeffeler
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Klein
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fehr
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Biskup
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Müller
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Winter
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: U M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.|Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: A T
authors.initials: AT
authors.lastname: Nies
mesh_terms: D001692:Biological Transport; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D020125:Mutation, Missense; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D017035:Pravastatin / Q000378:metabolism*; D014162:Transfection; D044465:White People / Q000235:genetics
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; C498886:SLC22A9 protein, human; D017035:Pravastatin