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

The Pharmacogenomics Journal volume 11, pages 25–34 (2011)Cite this article

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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.

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References

  1. Cascorbi I . Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 2006; 112: 457–473.

    Article  CAS  PubMed  Google Scholar 

  2. Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 2007; 63: 1161–1169.

    Article  CAS  PubMed  Google Scholar 

  3. Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y . Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 2006; 82: 1074–1084.

    Article  CAS  PubMed  Google Scholar 

  4. Rau T, Erney B, Gores R, Eschenhagen T, Beck J, Langer T . High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 2006; 80: 468–476.

    Article  CAS  PubMed  Google Scholar 

  5. Haenisch S, Zimmermann U, Dazert E, Wruck CJ, Dazert P, Siegmund W et al. Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex. Pharmacogenomics J 2007; 7: 56–65.

    Article  CAS  PubMed  Google Scholar 

  6. Han JY, Lim HS, Yoo YK, Shin ES, Park YH, Lee SY et al. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer 2007; 110: 138–147.

    Article  PubMed  Google Scholar 

  7. Choi JH, Ahn BM, Yi J, Lee JH, Lee JH, Nam SW et al. MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genomics 2007; 17: 403–415.

    Article  CAS  PubMed  Google Scholar 

  8. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP . Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007; 132: 272–281.

    Article  CAS  PubMed  Google Scholar 

  9. Haenisch S, May K, Wegner D, Caliebe A, Cascorbi I, Siegmund W . Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol. Pharmacogenet Genomics 2008; 18: 357–365.

    Article  CAS  PubMed  Google Scholar 

  10. Renders L, Frisman M, Ufer M, Mosyagin I, Haenisch S, Ott U et al. CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin Pharmacol Ther 2007; 81: 228–234.

    Article  CAS  PubMed  Google Scholar 

  11. Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 2008; 35: 572–579.

    CAS  PubMed  Google Scholar 

  12. Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramirez J, Relling M et al. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 2009; 27: 2604–2614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Meier Y, Pauli-Magnus C, Zanger UM, Klein K, Schaeffeler E, Nussler AK et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 2006; 44: 62–74.

    Article  CAS  PubMed  Google Scholar 

  14. Niemi M, Arnold KA, Backman JT, Pasanen MK, Godtel-Armbrust U, Wojnowski L et al. Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet Genomics 2006; 16: 801–808.

    Article  CAS  PubMed  Google Scholar 

  15. Zuker M . Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 2003; 31: 3406–3415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006; 314: 1930–1933.

    Article  CAS  PubMed  Google Scholar 

  17. Sharp PM, Tuohy TM, Mosurski KR . Codon usage in yeast: cluster analysis clearly differentiates highly and lowly expressed genes. Nucleic Acids Res 1986; 14: 5125–5143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315: 525–528.

    Article  CAS  Google Scholar 

  19. Day DA, Tuite MF . Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview. J Endocrinol 1998; 157: 361–371.

    Article  CAS  PubMed  Google Scholar 

  20. Sookoian S, Castano G, Burgueno A, Gianotti TF, Pirola CJ . Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy. J Hepatol 2008; 48: 125–132.

    Article  CAS  PubMed  Google Scholar 

  21. Hoblinger A, Grunhage F, Sauerbruch T, Lammert F . Association of the c.3972C>T variant of the multidrug resistance-associated protein 2 gene (MRP2/ABCC2) with susceptibility to bile duct cancer. Digestion 2009; 80: 36–39.

    Article  CAS  PubMed  Google Scholar 

  22. Hirouchi M, Suzuki H, Itoda M, Ozawa S, Sawada J, Ieiri I et al. Characterization of the cellular localization, expression level, and function of SNP variants of MRP2/ABCC2. Pharm Res 2004; 21: 742–748.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The technical assistance of Marion Pauer and Micheline Neubert is gratefully acknowledged.

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    S Laechelt, E Turrini, A Ruehmkorf, I Cascorbi & S Haenisch

  2. Division of Clinical Pharmacology, Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany

    W Siegmund

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  1. S Laechelt
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  2. E Turrini
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  4. W Siegmund
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Correspondence to S Haenisch.

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Laechelt, S., Turrini, E., Ruehmkorf, A. et al. Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function. Pharmacogenomics J 11, 25–34 (2011). https://doi.org/10.1038/tpj.2010.20

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  • DOI: https://doi.org/10.1038/tpj.2010.20

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