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

• Published in: The pharmacogenomics journal Vol. 11; no. 1; pp. 25 - 34
• Main Authors: Laechelt, S, Turrini, E, Ruehmkorf, A, Siegmund, W, Cascorbi, I, Haenisch, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2011; Nature Publishing Group
• Subjects: 631/208/200; 631/208/212/1728; 631/92/436/1729; Adrenergic beta-Antagonists - pharmacokinetics; Adult; Animals; Bioavailability; Biological Availability; Biomedical and Life Sciences; Biomedicine; Caco-2 Cells; Cell Line, Transformed; Cell lines; Deoxyribonucleic acid; DNA; Dogs; Female; Fluorescent indicators; Gene Expression; Gene Expression Regulation; Gene regulation; Genetic diversity; Genetic regulation; Genetic transcription; Genetic Variation; Glutathione; Haplotypes; HEK293 Cells; Human Genetics; Humans; Male; Membrane Transport Proteins - biosynthesis; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; mRNA stability; Multidrug Resistance-Associated Proteins - biosynthesis; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Oncology; original-article; Pharmacotherapy; Polymorphism, Single Nucleotide; Post-transcription; Propanolamines - pharmacokinetics; Protein Binding; Protein expression; Protein structure; Protein transport; Proteins; Psychopharmacology; RNA Processing, Post-Transcriptional; RNA, Messenger - genetics; RNA, Messenger - metabolism; Secondary structure; Transfection; Young Adult; Germany; drug distribution; polymorphism; ABC transporters; MRP2; haplotype; pharmacogenetics
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2010.20

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.