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Type: Journal article
Title: Variability in human hepatic MRP4 expression: Influence of cholestasis and genotype
Author: Gradhand, U.
Lang, T.
Schaeffeler, E.
Glaeser, H.
Tegude, H.
Klein, K.
Fritz, P.
Jedlitschky, G.
Kroemer, H.
Bachmakov, I.
Anwald, B.
Kerb, R.
Zanger, U.
Eichelbaum, M.
Schwab, M.
Fromm, M.
Citation: The Pharmacogenomics Journal, 2008; 8(1):42-52
Publisher: Nature Publishing Group
Issue Date: 2008
ISSN: 1470-269X
Statement of
U. Gradhand, T. Lang, E. Schaeffeler, H. Glaeser, H. Tegude, K. Klein, P. Fritz, G. Jedlitschky, H.K. Kroemer, I. Bachmakov, B. Anwald, R. Kerb, U.M. Zanger, M. Eichelbaum, M. Schwab and M.F. Fromm
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: 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.
Keywords: MRP4; ABCC4; single nucleotide polymorphism; multidrug resistance; cholestasis; expression
RMID: 0020084887
DOI: 10.1038/sj.tpj.6500451
Appears in Collections:Pharmacology publications

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