Prospects of using C3435T polymorphism in the ABCB1 gene encoding P-glycoprotein in personalised medicine

The article reviews scientific literature on C3435T polymorphism in the ABCB1 gene which encodes P-glycoprotein (an ATP-binding cassette transporter which is responsible for energy-dependent transport of substrates across cellular membranes and whose primary role consists in the prevention of penetration of various substances, such as xenobiotics, through biological barriers. C3435T polymorphism in the ABCB1 gene could be regarded as a promising pharmacogenetic biomarker which could be used in diagnostic testing after approval of the corresponding test methods. The authors of the article collected and systematized scientific data available in the electronic media (NCBI PubMed, eLIBRARY.ru) regarding medicines (such as digoxin, fexofenadine, loperamide, amlodipine, statins, etc.) for which there are integrated pharmacogenetic data on the effect of C3435T polymorphism in the ABCB1 gene on pharmacokinetic parameters, as well as on the efficacy and safety of treatment. It was demonstrated that ABCB1 gene polymorphism is of great importance for personalised medicine, however, there is a lack of awareness about all the factors that affect the bioavailability of medicines, and this precludes a significant progress in the use of ABCB1 genotyping in the near future.

персонализированная медицина, генетический полиморфизм, P-гликопротеин, однонуклеотидные полиморфизмы, АТФ-связывающие кассетные транспортеры, personalised medicine, genetic polymorphism, P-glycoprotein, single nucleotide polymorphisms, ATP-binding cassette transporters

1. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene 2003; 22(47): 7468–85.

2. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13(8): 481–94.

3. Takane H, Kobayashi D, Hirota T, Kigawa J, Terakawa N, Otsubo K, et al. Haplotype-oriented genetic analysis and functional assessment of promoter variants in the MDR1 (ABCB1) gene. J Pharmacol Exp Ther. 2004; 311(3): 1179–87.

4. Romanov BK. Regulation of myocardial lysosomal enzyme activity by calcium. Biomedical Chemistry 2005; 51(6): 634–42 (in Russian).

5. Li Y, Wang Y, Sun J, Li Y, Yang L. Distribution of the functional MDR1 C3435T polymorphism in the Han population of China. Swiss Med Wkly. 2006; 136(23–24): 377–82.

6. Takara K, Takagi K, Tsujimoto M, Ohnishi N, Yokoyama T. Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA. Biochem Biophys Res Commun. 2003; 306(1): 116–20.

7. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97(7): 3473–8.

8. Chowbay B, Li H, David M, Cheung YB, Lee EJ. Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol. 2005; 60(2): 159–71.

9. Sychev DA, Ignatiev IV, Andreev DA, Poshukaeva LG, Kolkhir PV, Zhukova EE, et al. Glycoprotein P pharmacogenetic assessment role in digoxin pharmacotherapy individualization: a new approach for an old problem. Russian Journal of Cardiology 2006; (4): 64–8 (in Russian).

10. Drozdzik M, Rudas T, Pawlik A, Kurzawski M, Czerny B, Gornik W, et al. The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with isease-modifying antirheumatic drugs. Eur J Clin Pharmacol. 2006; 62(11): 933–7.

11. Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol. 2002; 53(5): 526–34.

12. Yi SY, Hong KS, Lim HS, Chung JY, Oh DS, Kim JR, et al. A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clin Pharmacol Ther. 2004; 76(5): 418–27.

13. Goreva OB, Grishanova AY, Mukhin OV, Domnikova NP, Lyakhovich VV. Possible prediction of the efficiency of chemotherapy in patients with lymphoproliferative diseases based on MDR1 gene G2677T and C3435T polymorphisms. Bull Exp Biol Med. 2003; 136(2): 183–5.

14. Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002; 74(4): 571–2.

15. Goto M, Masuda S, Saito H, Uemoto S, Kiuchi T, Tanaka K, et al. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 2002; 12(6): 451–7.

16. Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P- glycoprotein): Recent advances and clinical relevance. Clin Pharmacol Ther. 2004; 75(1): 13–33.

17. Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, et al. Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 2003; 13(11): 651–60.

18. Pauli-Magnus C, Feiner J, Brett C, Lin E, Kroetz DL. No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects. Clin Pharmacol Ther. 2003; 74(5): 487–98.

19. Kim KA, Park PW, Park JY. Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. Br J Clin Pharmacol. 2007; 63(1): 53–8.

20. Zuo XC, Zhang WL, Yuan H, Barrett JS, Hua Y, Huang ZJ, et al. ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis. Drug Metab Pharmacokinet. 2014; 29(4): 305–11.

21. Semenov AV, Sychev DA, Kukes VG. Effect of genes SLCO1B1 and MDR1 polymorphism on atorvastatin pharmacokinetics and pharmacodynamics in patients with primary hypercholesterolemia: results of pilot pharmacogenetics study. Rational Pharmacother Card. 2008; (2): 47–50 (in Russian).

22. Su J, Xu H, Yang J, Yu Q, Yang S, Zhang J, et al. ABCB1 C3435T polymorphism and the lipid-lowering response in hypercholesterolemic patients on statins: a meta- analysis. Lipids Health Dis. 2015; 14: 122.

23. McBride BF, Yang T, Roden DM. Influence of the G2677T/C3435T haplotype of MDR1 on P-glycoprotein trafficking and ibutilide-induced block of HERG. Pharmacogenomics J. 2009; 9(3): 194–201.

24. Sokova EA. Monitoring post-approvial drug safety in pregnancy: pharmacogenetic aspects. Safety and Risk of Pharmacotherapy 2015; (3): 30–5 (in Russian).