| Autor: |
Emami Riedmaier, A, Burk, O, van Eijck, B A C, Schaeffeler, E, Klein, K, Fehr, S, Biskup, S, Müller, S, Winter, S, Zanger, U M, Schwab, M, Nies, A T |
| Zdroj: |
The Pharmacogenomics Journal; August 2016, Vol. 16 Issue: 4 p341-351, 11p |
| Abstrakt: |
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 SLC22A9were 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 (HNF4a) emerged as a major transcriptional regulator of SLC22A9by a series of in silicoand in vitroanalyses. In conclusion, pravastatin is the first identified OAT7 drug substrate. Substantial inter-individual variability in hepatic OAT7 expression, majorly driven by HNF4a, may contribute to pravastatin drug disposition and might affect response. |
| Databáze: |
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