TITLE

Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function

AUTHOR(S)
Laechelt, S; Turrini, E; Ruehmkorf, A; Siegmund, W; Cascorbi, I; Haenisch, S
PUB. DATE
February 2011
SOURCE
Pharmacogenomics Journal;Feb2011, Vol. 11 Issue 1, p25
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
ABCC2 (MRP2) is an important export pump, expressed at tissue barriers. The genetic variants −24C>T, 1249G>A and 3972C>T are leading to inter-individual differences of bioavailability of various endogenous and exogenous compounds. Considering ABCC2 haplotypes, we investigated DNA-protein binding properties, mRNA secondary structure, mRNA stability, protein expression and transport activity in various cell lines and analyzed the bioavailability of talinolol in 24 healthy Caucasian volunteers; −24C>T had no clear influence on DNA-protein binding and the mRNA stability did not differ significantly. In transfected HEK293T/17 cells, haplotypes H9 (CGT), H10 (TGC) and H12 (TGT) had significantly lower protein expression, whereas H2 (CAC) exhibited significantly increased protein expression compared to the wild type (H1, CGC): 32.7±8.8, 73.1±6.3; 44.0±15.5 and 115.2±8.2%, respectively. This corresponded with efflux rates of the fluorescent dye glutathione-methylfluorescein in vitro and by trend with talinolol bioavailability in vivo. In conclusion our results show a haplotype-dependent influence on transport capacity of ABCC2, which seems to be mainly based on posttranscriptional modification of protein expression rather than transport rates.
ACCESSION #
57544951

 

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