Characterization of the Cellular Localization, Expression Level, and Function of SNP Variants of MRP2/ABCC2

Hirouchi, Masakazu; Suzuki, Hiroshi; Itoda, Masaya; Ozawa, Shogo; Sawada, Jun Ichi; Ieiri, Ichiro; Ohtsubo, Kenji; Sugiyama, Yuichi

doi:10.1023/b:pham.0000026422.06207.33

Cited by 104 publications

(61 citation statements)

References 27 publications

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“…21 The impact of the haplotypes on ABCC2 protein expression was clearly mirrored in the transport rates of the fluorescent dye glutathione-methylfluorescein, indicating that the protein expression rather than transport activity altered the efflux rates. This is in line with findings of Hirouchi et al 22 showing no differences in transport activity after normalization on protein expression at least concerning the 1249G4A polymorphism. Moreover, theses findings are subsidized by the re-analysis of talinolol pharmacokinetic in healthy volunteers.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2010

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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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2010

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“…No data suggest that the presence of infrequent SNP in the MRP2 gene may be associated with a decrease in the in vivo function of the transporter. 12 Thus, MRP2 may participate in the transport of the pruritogen(s) or its cofactors in cholestasis. Possible mechanisms by which V1188E affects the development of pruritus of cholestasis include alterations in the transport of pruritogen(s) or its cofactors from the hepatocyte into bile or into the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus

et al. 2006

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“…Two aliquots of at least 0.7 ml of plasma each were removed, placed in screw-cap polypropylene tubes and immediately stored at À20 1C or below until the analysis. Blood samples were collected before and at 0.5, 1, 1.5, 2, 3, 4,6,8,12,16,24,36,48,60 and 72 h following each dose. The plasma concentrations of olmesartan were determined by a validated method of high-performance liquid chromatography with fluorescence detection.…”

Section: Sample Treatments and Pharmacokinetic Data Analysismentioning

confidence: 99%

“…[12][13][14] Beside mutations in Dubin-Johnson syndrome, the extensive genetic variation identified so far may have a potential effect on drug disposition. 15,16 In fact, the T allele of À24C4T has been associated with lower mRNA levels in normal renal tissues, leading to reduced transporter activity. 17 In addition, the synonymous mutation 1446C4G was associated with increased hepatic mRNA expression resulting in low C max and area under the plasma concentration time curve (AUC) values for pravastatin.…”

Section: Introductionmentioning

confidence: 99%

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

et al. 2012

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It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5 0 and 3 0 flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of X0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.

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Characterization of the Cellular Localization, Expression Level, and Function of SNP Variants of MRP2/ABCC2

Abstract: These results suggest that the most frequently observed V417I substitution may not affect the in vivo function of MRP2, whereas the much less frequently observed S789F and A1450T may be associated with the reduced in vivo function.

Cited by 104 publications

References 27 publications

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

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

A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

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