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

The Pharmacogenomics Journal volume 16, pages 341–351 (2016)Cite this article

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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.

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Acknowledgements

We would like to acknowledge the expert technical assistance of Silvia Hübner, Monika Elbl, Heidi Köhler, Igor Liebermann, Karina Abuazi and Sabine Rekersbrink. We would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). This work was supported by grants from the Robert-Bosch Foundation, Stuttgart, Germany, the 7th FP EU Initial Training Network program ‘FightingDrugFailure’ (PITN-GA-2009-238132) and the Federal Ministry for Education and Research (BMBF, Berlin, Germany) grant 0315755.

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Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    A Emami Riedmaier, O Burk, B A C van Eijck, E Schaeffeler, K Klein, S Müller, S Winter, U M Zanger, M Schwab & A T Nies

  2. University of Tübingen, Tübingen, Germany

    A Emami Riedmaier, O Burk, B A C van Eijck, E Schaeffeler, K Klein, S Müller, S Winter, U M Zanger, M Schwab & A T Nies

  3. CeGaT GmbH, Tübingen, Germany

    S Fehr & S Biskup

  4. Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany

    M Schwab

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Emami Riedmaier, A., Burk, O., van Eijck, B. et al. Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors. Pharmacogenomics J 16, 341–351 (2016). https://doi.org/10.1038/tpj.2015.55

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