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

Abstract

ABCC2 (MRP2) is an important export pump, expressed at tissue barriers. The genetic variants À24C4T, 1249G4A and 3972C4T 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; À24C4T 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 haplotypedependent influence on transport capacity of ABCC2, which seems to be mainly based on posttranscriptional modification of protein expression rather than transport rates.

Genetic and biochemical study of dual hereditary jaundice: Dubin–Johnson and Gilbert’s syndromes. Haplotyping and founder effect of deletion in ABCC2

“…Several haplotype analyses of ABCC2 have been performed due to its pharmacogenomic impact, even one concerning the impact of ABCC2 haplotype on coproporphyrin excretion, but only using SNPs with proven pharmacogenomics effect. 36,37 There are more than 130 SNPs within ABCC2 and their importance in vitro has mostly not been described yet. Our study clearly shows, that in addition to the ABCC2 haplotype, which is shared in our DJS patients, other factors may also influence coproporphyrin excretion in urine, such as SNPs in other genes or undiscovered environmental factors.…”

Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment

“…with C-24T [18] or with other SNPs in ABCC2 gene that form different ABCC2 haplotypes [19]. Our hypothesis was that raloxifene and / or its glucuronides might be substrates for ABC transporters, from which we selected the ones that were most frequently associated with significant impact on pharmacokinetics of various other drugs, namely, Pgp, MRP1, MRP2, MRP3 and BCRP.…”

“…Nevertheless, it has been published that ABCB1 c.3435C>T polymorphism influences the pharmacokinetics of paclitaxel [14], cyclosporine [15], phenobarbital [16], nelfinavir [17] and some other drugs. ABCC2 c.3972C>T is a silent single nucleotide polymorphism (SNP) without any effect on amino acid translation thus the influence of this polymorphism on pharmacokinetics is possibly mediated through a linkage disequilibrium with C-24T [18] or with other SNPs in ABCC2 gene that form different ABCC2 haplotypes [19]. Our hypothesis was that raloxifene and / or its glucuronides might be substrates for ABC transporters, from which we selected the ones that were most frequently associated with significant impact on pharmacokinetics of various other drugs, namely, Pgp, MRP1, MRP2, MRP3 and BCRP.…”

Pharmacogenetics: The Scientific Basis

“…(MRP2) is an export pump expressed at tissue barriers. Genetic variants 24 e>T, 1249Ca>A and 3972 > T had been observed and are thought to cause inter individual differences of bioavailability of various endogenous and exogenous compounds (Colombo et al 2005, Laechelt et al 2011. About 27 other variants have also been detected (Colombo et al 2005).…”

“…About 27 other variants have also been detected (Colombo et al 2005). A haplotype dependent influence on transport capacity of ABCC2 had been observed but seems to be mainly based on post transcriptional modifications rather than transport rates (Laechelt et al 2011).…”