Gradhand U, Lang T, Schaeffeler E, Glaeser H, Tegude H, Klein K, Fritz P, Jedlitschky G, Kroemer H K, Bachmakov I, Anwald B, Kerb R, Zanger U M, Eichelbaum M, Schwab M, Fromm M F
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstrasse 17, Erlangen, Germany.
Pharmacogenomics J. 2008 Feb;8(1):42-52. doi: 10.1038/sj.tpj.6500451. Epub 2007 Apr 3.
The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5'-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299+/-138 vs 100+/-60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.
多药耐药蛋白4（MRP4）是一种外排转运蛋白，参与内源性底物和外源性物质的转运。我们检测了人肝脏中MRP4的mRNA和蛋白表达，发现其变异倍数分别为38倍和45倍。我们对95例患者的MRP4基因5'侧翼区2 kb、所有外显子及内含子/外显子边界进行了测序，共鉴定出74个基因变异，其中包括10个非同义变异，其中7个位于高度保守区域。所检测到的多态性均与MRP4 mRNA或蛋白表达的变化无显著相关性。免疫荧光显微镜检查表明，所有非同义变异均未影响MRP4的细胞定位。然而，与非胆汁淤积性肝脏相比，胆汁淤积性患者的MRP4 mRNA和蛋白表达均显著上调（蛋白：299±138 vs 100±60任意单位，P<0.001）。综上所述，人肝脏中MRP4的表达高度可变。基因变异不足以解释这种变异性。相反，胆汁淤积是人类肝脏MRP4表达的一个主要决定因素。
