1. ¹Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
2. ²Institute of Pharmacology, University of Mainz, Mainz, Germany
3. ³Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany
4. ⁴Department of Pathology, Robert-Bosch-Hospital, Stuttgart Tuebingen, Tuebingen, Germany
5. ⁵Department of Pharmacology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany
6. ⁶Epidauros Biotechnology, Pharmacogenetics Laboratory, Am Neuland 1, Bernried, Germany
7. ⁷Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany

Correspondence: Dr MF Fromm, Institute of Clinical and Experimental Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstrasse 17, 91054 Erlangen, Germany. E-mail: martin.fromm@pharmakologie.med.uni-erlangen.de

Received 17 October 2006; Revised 18 December 2006; Accepted 16 February 2007; Published online 3 April 2007.

Abstract

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: 299138 vs 10060a.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.