Allele Frequency of Carbamazepine Major Efflux Transporter Encoding Gene ABCB1 C3435T among Javanese-Indonesian Population


  • Rochmy Istikharah Department of Pharmacy, Laboratory of Biochemistry, Universitas Islam Indonesia, Yogyakarta, Indonesia
  • Septiayu D. Hartienah Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia
  • Sandra Vitriyani Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia
  • Vitarani Dwi Ananda Ningrum Department of Pharmacy, Laboratory of Pharmaceutical Research, Universitas Islam Indonesia, Yogyakarta, Indonesia



Carbamazepine, ABCB1 C3435T, Javanese-Indonesian population


BACKGROUND: Genetic variations in ABCB1 gene that encodes P-glycoprotein, the main transporter in the efflux of carbamazepine (CBZ) from the brain cells, can lead to pharmacodynamic and pharmacokinetic variability. Polymorphism of C3435T is widely known to cause protein overexpression that contributes to an increased risk of CBZ resistance.

AIM: This study determined the allele frequency distribution of ABCB1 C3435T gene in healthy subjects of the Javanese population as a major ethnic group in Indonesia.

METHODS: This cross-sectional study involved 100 healthy volunteers who fulfilled the inclusion criteria. The genotype analysis to detect polymorphism in the targets employed the polymerase chain reaction-restriction fragment length polymorphism method with 5’-TGCTGGTCCTGAAGTTGATCTGTGAAC-3’ as the forward primer and 5’-ACATTAGGCAGTGACTCGATGAAGGCA-3’ as the reverse primer.

RESULTS: The frequency of subjects with C allele in ABCB1 C3435T gene reached 53%, higher than that with T allele.

CONCLUSION: This finding was nearly the same as that in studies of the populations in China, Turkey, and four countries in the South European continent. It is recommended to conduct further research on the correlation between C3435T polymorphism and CBZ dose variability to provide a comprehensive approach to epilepsy management in patients receiving CBZ.


Download data is not yet available.


Metrics Loading ...

Plum Analytics Artifact Widget Block


Löscher W, Klotz U, Zimprich F, Schmidt D. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia. 2009;50(1):1-23. https://doi. org/10.1111/j.1528-1167.2008.01716.x PMid:18627414

PERDOSSI. Pedoman Tatalaksana Epilepsi. 5th ed. Surabaya: Airlangga Unversity Press; 2014.

Kemenkes RI. Formularium Nasional. Jakarta: Kementrian Kesehatan Republik Indonesia; 2017.

Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv Drug Deliv Rev. 2003;55(1):3-29. PMid:12535572

FDA. Information for Healthcare Professionals: Dangerous or Even Fatal Skin Reactions Carbamazepine (Marketed as Carbatrol, Equetro, Tegretol, and Generics). Adv FDA’s Saf Program Mark Drugs; 2012. Available from: postmarketdrugsafetyinformationforpatientsandproviders/ ucm124718.htm. [Last accessed on 2018 Jan 22].

Yuliwulandari R, Kashiwase K, Nakajima H, Uddin J, Susmiarsih TP, Sofro AS, et al. Polymorphisms of HLA genes in Western Javanese (Indonesia): Close affinities to Southeast Asian populations. Tissue Antigens 2009;73(1):46-53. https:// PMid:19140832

Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314-9. NEJM200002033420503 PMid:10660394

Sisodiya SM, Goldstein DB. Drug resistance in epilepsy: More twists in the tale. Epilepsia. 2007;48(12):2369-70. https://doi. org/10.1111/j.1528-1167.2007.01260_1.x PMid:18088268

Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42(10):1255-60. https://doi. org/10.1046/j.1528-1157.2001.04501.x PMid:11737159

Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther Drug Monit. 2000;22(1):137-40. https://doi. org/10.1097/00007691-200002000-00029 PMid:10688277

Seo T, Ishitsu T, Ueda N, Nakada N, Yurube K, Ueda K, et al. ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics. 2006;7(4):551-61. PMid:16753003

Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003;348(15):1442-8. https://doi. org/10.1056/NEJMoa021986 PMid:12686700

Meng H, Guo G, Ren J, Zhou H, Ge Y, Guo Y. Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy. Epilepsy Behav. 2011;21(1):27-30. yebeh.2011.02.015. PMid:21493161

Ozgon GO, Bebek N, Gul G, Cine N. Association of MDR1 (C3435T) polymorphism and resistance to carbamazepine in epileptic patients from Turkey. Eur Neurol. 2008;59(1-2):67-70. PMid:17917461

Holsinger KE. Hardy Weinberg law. In: Encyclopedia of Genetics. Amsterdam, Netherlands: Elsevier; 2001. p. 912-4.

Rogers AJ, Weiss ST. Epidemiologic and population genetic studies. In: Robertson D, Williams GH, editors. Clinical and Translation Science: Principles of Human Research. United Kingdom: Elsevier; 2017. p. 313-26. b978-0-12-802101-9.00017-x

Bebawy M, Chetty M. Gender differences in p-glycoprotein expression and function: Effects on drug disposition and outcome. Curr Drug Metab. 2009;10(4):322-8. https://doi. org/10.2174/138920009788498996 PMid:19519340

Leschziner GD, Andrew T, Pirmohamed M, Johnson MR. ABCB1 genotype and PGP expression, function and therapeutic drug response: A critical review and recommendations for future research. Pharmacogenomics J. 2007;7(3):154-79. https://doi. org/10.1038/sj.tpj.6500413 PMid:16969364

Romiti N, Tramonti G, Donati A, Chieli E. Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK-2. Life Sci. 2004;76(3):293-302. PMid:15531381

Marino S, Birnbaum A, Leppik I, Conway J, Musib L, Brundage R, et al. Steady-state carbamazepine pharmacokinetics following oral and stable-labeled intravenous administration in epilepsy patients: Effect of race and sex. Clin Pharmacol Ther. 2012;91(3):483-8. PMid:22278332

Zhu X, Yun W, Sun X, Qiu F, Zhao L, Guo Y. Effects of major transporter and metabolizing enzyme gene polymorphisms on carbamazepine metabolism in Chinese patients with epilepsy. Pharmacogenomics. 2014;15(15):1867-79. https://doi. org/10.2217/pgs.14.142 PMid:25495409

Gong XD, Wang JY, Liu F, Yuan HH, Zhang WY, Guo YH, et al. Gene polymorphisms of OPRM1 A118G and ABCB1 C3435T may influence opioid requirements in chinese patients with cancer pain. Asian Pac J Cancer Prev. 2013;14(5):2937-43. PMid:23803057

Shan XX, Qiu Y, Xie WW, Wu RR, Yu Y, Wu HS, et al. ABCB1 gene is associated with clinical response to SNRIs in a local chinese han population. Front Pharmacol. 2019;10:761. https:// PMid:31333472

Yan RJ, Lou TT, Wu YF, Chen WS. Single nucleotide polymorphisms of ABCB1 gene and response to etanercept treatment in patients with ankylosing spondylitis in a Chinese Han population. Medicine (Baltimore). 2017;96(5):e5929. PMid:28151874

Zhao Z, Lv B, Zhao X, Zhang Y. Effects of OPRM1 and ABCB1 gene polymorphisms on the analgesic effect and dose of sufentanil after thoracoscopic-assisted radical resection of lung cancer. Biosci Rep. 2019;39(1):BSR20181211. https://doi. org/10.1042/BSR20181211 PMid:30455395

Chang HH, Chou CH, Yang YK, Lee IH, Chen PS. Association between ABCB1 polymorphisms and antidepressant treatment response in Taiwanese major depressive patients. Clin Psychopharmacol Neurosci. 2015;13(3):250-5. https://doi. org/10.9758/cpn.2015.13.3.250 PMid:26598582

Komoto C, Nakamura T, Sakaeda T, Kroetz DL, Yamada T, Omatsu H, et al. MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer. Drug Metab Pharmacokinet. 2006;21(2):126-32. PMid:16702732

Ozbey G, Yucel B, Taycan SE, Kan D, Bodur NE, Arslan T, et al. ABCB1 C3435T polymorphism is associated with susceptibility to major depression, but not with a clinical response to citalopram in a Turkish population. Pharmacol Rep. 2014;66(2):235-8. PMid:24911075

Hosseini M, Ebrahimi A, Houshmand M, Zainali S, Tonekaboni SH, Moghaddasi M. SCN1A and ABCB1 polymorphisms in epilepsy. Arch Neurosci. 2018;5(1):e59383.

Talaat RM, El-Kelliny MK, El-Akhras BA, Bakry RM, Riad KF, Guirgis AA. Association of C3435T, C1236T and C4125A polymorphisms of the MDR-1 gene in Egyptian children with acute lymphoblastic leukaemia. Asian Pac J Cancer Prev. 2018;19(9):2535-43. APJCP.2018.19.9.2535 PMid:30256048

Balan S, Bharathan SP, Vellichiramal NN, Sathyan S, Joseph V, Radhakrishnan K, et al. Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance. PLoS One. 2014;9(2):e89253. https://doi. org/10.1371/journal.pone.0089253 PMid:24586633

Sipeky C, Csongei V, Jaromi L, Safrany E, Maasz A, Takacs I, et al. Genetic variability and haplotype profile of MDR1 (ABCB1) in Roma and Hungarian population samples with a review of the literature. Drug Metab Pharmacokinet. 2011;26(2):206-15. PMid:21178299

Rychlik-Sych M, Barańska M, Dudarewicz M, Skrętkowicz J, Żebrowska A, Woźniacka A, et al. Haplotypes of ABCB1 1236C >T (rs1128503), 2677G >T/A (rs2032582), and 3435C >T (rs1045642) in patients with bullous pemphigoid. Arch Dermatol Res. 2018;310(6):515-22. s00403-018-1842-8 PMid:29948283

Jeleń AM, Sałagacka A, Żebrowska MK, Mirowski M, Talarowska M, Gałecki P, et al. The influence of C3435T polymorphism of the ABCB1 gene on genetic susceptibility to depression and treatment response in polish population preliminary report. Int J Med Sci 2015;12(12):974-9. https://doi. org/10.7150/ijms.13119 PMid:26664259

Sabin O, Pop R, Trifa A, Buzoianu AD. The Influence of CYP2C9, CYP2C19 and ABCB1 Polymorphisms on the Plasma Concentrations of Valproic Acid in Epileptic Patients. Vol. 8; 2016. p. 5.

Basic S, Hajnsek S, Bozina N, Filipcic I, Sporis D, Mislov D, et al. The influence of C3435T polymorphism of ABCB1 gene on penetration of phenobarbital across the blood brain barrier in patients with generalized epilepsy. 2008;17(6):524-30. https:// PMid:18329296

Nóvoa SR, Barreiro P, Rendón A, Barrios A, Corral A, Jiménez-Nacher I, et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C→T polymorphism at the multidrug resistance gene 1. Clin Infect Dis. 2006;42(2):291-5. PMid:16355344

Santos M, Carvalho S, Lima L, Nogueira A, Assis J, Mota- Pereira J, et al. Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male portuguese individuals. Genet Test Mol Biomark. 2013;18(1):12-9. PMid:24200053

Rafiee R, Chauhan L, Alonzo TA, Wang YC, Elmasry A, Loken MR, et al. ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin: A report from children’s oncology group AAML0531 Trial. Blood Cancer J. 2019;9:1127. s41408-019-0211-y

Bouatou Y, Stenz L, Ponte B, Ferrari S, Paoloni-Giacobino A, Hadaya K. Recipient rs1045642 polymorphism is associated with office blood pressure at 1-year post kidney transplantation: A single center pharmacogenetic cohort pilot study. Front Pharmacol. 2018;9:184. fphar.2018.00184 PMid:29556197

Razi B, Sarab GA, Omidkhoda A, Alizadeh S. Multidrug resistance 1 (MDR1/ABCB1) gene polymorphism (rs1045642 C> T) and susceptibility to multiple myeloma: A systematic review and meta-analysis. Hematology. 2018;23(8):456-62. PMid:29495954

Sychev D, Shikh N, Morozova T, Grishina E, Ryzhikova K, Malova E. Effects of ABCB1 rs1045642 polymorphisms on the efficacy and safety of amlodipine therapy in Caucasian patients with stage I-II hypertension. Pharmacogenomics Pers Med. 2018;11:157-65. PMid:30288082

Sychev DA, Levanov AN, Shelekhova TV, Bochkov PO, Denisenko NP, Ryzhikova KA, et al. The impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty. Pharmacogenomics Pers Med. 2018;11:127-37. PMid:30100750

Hattori S, Suda A, Kishida I, Miyauchi M, Shiraishi Y, Fujibayashi M, et al. Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia. BMC Psychiatry. 2018;18(1):231. PMid:30016952

Kiaco K, Rodrigues AS, do Rosário V, Gil JP, Lopes D. The drug transporter ABCB1 c.3435C>T SNP influences artemether– lumefantrine treatment outcome. Malar J. 2017;16(1):383. PMid:28934955

Sałagacka A, Bartczak M, Zebrowska M, Jażdżyk M, Balcerczak M, Janiuk R, et al. C3435T polymorphism of the ABCB1 gene: Impact on genetic susceptibility to peptic ulcers. Pharmacol Rep. 2011;63(4):992-8. s1734-1140(11)70615-6 PMid:22001987

Saiz-Rodríguez M, Belmonte C, Román M, Ochoa D, Jiang- Zheng C, Koller D, et al. Effect of ABCB1 C3435T polymorphism on pharmacokinetics of antipsychotics and antidepressants. Basic Clin Pharmacol Toxicol. 2018;123(4):474-85. https://doi. org/10.1111/bcpt.13031 PMid:29723928

Li S, Liu Y, Wang Q. ABCB1 gene C3435T polymorphism and drug resistance in epilepsy: Evidence based on 8604 subjects. Med Sci. 2015;21:861-8. PMid:25799371

Chouchi M, Kaabachi W, Klaa H, Tizaoui K, Turki IB, Hila L. Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in epilepsy: Updated systematic review and meta-analysis. BMC Neurol. 2017;17(1):32. https:// PMid:28202008

Tazzite A, Kassogue Y, Diakité B, Jouhadi H, Dehbi H, Benider A, et al. Association between ABCB1 C3435T polymorphism and breast cancer risk: A Moroccan case-control study and meta-analysis. BMC Genet. 2016;17(1):126. s12863-016-0434-x PMid:27580695

Ma L, Ruan L, Liu H, Yang H, Feng Y. ABCB1 C3435T polymorphism is associated with leukemia susceptibility: Evidence from a meta-analysis. Onco Targets Ther. 2015;8:1009-15. PMid:25999734

Su J, Xu J, Li X, Zhang H, Hu J, Fang R, et al. ABCB1 C3435T polymorphism and response to clopidogrel treatment in coronary artery disease (CAD) patients: A meta-analysis. PLoS One. 2012;7(10):e46366. pone.0046366 PMid:23056288

Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain J Neurol. 2006;129(Pt 1):18-35. PMid:16317026




How to Cite

Istikharah R, Hartienah SD, Vitriyani S, Ningrum VDA. Allele Frequency of Carbamazepine Major Efflux Transporter Encoding Gene ABCB1 C3435T among Javanese-Indonesian Population. Open Access Maced J Med Sci [Internet]. 2020 Jul. 20 [cited 2022 Jul. 1];8(A):406-13. Available from: