European Journal of Clinical Pharmacology

, Volume 71, Issue 9, pp 1067–1073 | Cite as

CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy

  • Paulo Roberto Xavier Tomaz
  • Juliana Rocha Santos
  • Jaqueline Scholz Issa
  • Tânia Ogawa Abe
  • Patrícia Viviane Gaya
  • José Eduardo Krieger
  • Alexandre Costa PereiraEmail author
  • Paulo Caleb Júnior Lima SantosEmail author



Previous studies suggested that polymorphisms in the CYP2B6 gene (which encodes an isoenzyme that metabolizes bupropion) and in the ANKK1 gene (which is located in the ANKK1/DRD2 gene cluster) might influence response to therapy. Thus, the aim of the present study was to evaluate whether the CYP2B6 and ANKK1 polymorphisms are associated with the response to smoking cessation therapies in patients from a smoking cessation assistance program.


The cohort study enrolled 478 smokers who received behavioral counseling and drug therapy (bupropion, nicotine replacement therapy, and/or varenicline). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores were analyzed for nicotine dependence (ND). The ANKK1 rs1800497, CYP2B6*4 (rs2279343), CYP2B6*5 (rs3211371), and CYP2B6*9 (rs3745274) polymorphisms were genotyped by high resolution melting analysis or by restriction fragment length polymorphism.


Patients with CYP2B6 rs2279343 wild-type AA genotype had higher success rate (48.0 %) compared with patients carrying AG or GG genotypes (CYP2B6*4 variant) (35.5 %) on bupropion therapy. The AA genotype was associated with higher OR for success during bupropion therapy (OR = 1.92, 95 % CI = 1.08–3.42, p = 0.03) in a multivariate model. We did not observe significant differences in the FTND and Issa scores according to the studied polymorphisms.


We showed that patients with CYP2B6*4 (rs2279343) variant had lower success rate with bupropion. Likely, the CYP2B6*4 variant, which leads to a rapid predicted metabolic phenotype for the isoenzyme, influences the pharmacological activity of bupropion. Our finding suggests that CYP2B6*4 may be an important genetic marker for individualized bupropion pharmacotherapy.


Pharmacogenetics CYP2B6 gene ANKK1 gene Bupropion 



PCJL Santos is a recipient of fellowship and funding from FAPESP (Proc. 2013-09295-3 and Proc. 2013-20614-3) and from CNPq (Proc. 470410/2013-2), Brazil. PRX Tomaz is recipient of fellowship from CAPES, Brazil. JR Santos is a recipient of fellowship from CNPq, Proc. 167587/2013-7, Brazil. We also thank the patients who participated in the study. The technical assistance of the Laboratory of Genetics and Molecular Cardiology group, the FAPESP Proc. 2013/17368-0, and Sociedade Hospital Samaritano – Ministério da Saúde (PROADI-SUS; SIPAR: 25000.180.672/2011-81) are gratefully acknowledged.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

228_2015_1896_MOESM1_ESM.docx (12 kb)
ESM 1 Linkage disequilibrium and haplotype analysis for the CYP2B6 polymorphisms in the patients submitted to treatment for smoking cessation. In a haplotype analysis, the GAC and GAT haplotypes for the CYP2B6 were associated with smoking cessation success (p values: 0.04, 0.03, respectively). (DOCX 61 kb)
228_2015_1896_MOESM2_ESM.docx (13 kb)
ESM 2 Enzymes, reagents, and fragments for the polymorphisms. (DOCX 13 kb)
228_2015_1896_MOESM3_ESM.docx (61 kb)
ESM 3 Variables of the multiple linear regression model for FTND score. (DOCX 14 kb)


  1. 1.
    Hiilamo H, Glantz SA (2015) Implementation of effective cigarette health warning labels among low and middle income countries: state capacity, path-dependency and tobacco industry activity. Soc Sci Med 124C:241–245CrossRefGoogle Scholar
  2. 2.
    Tomioka H, Sekiya R, Nishio C, Ishimoto G. Impact of smoking cessation therapy on health-related quality of life. BMJ Open Respir Res 2014;1:e000047.Google Scholar
  3. 3.
    A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S. Public Health Service report. Am J Prev Med 2008;35:158-176.Google Scholar
  4. 4.
    Pine-Abata H, McNeill A, Murray R, Bitton A, Rigotti N, Raw M (2013) A survey of tobacco dependence treatment services in 121 countries. Addiction 108:1476–1484PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Kasza KA, Hyland AJ, Borland R, McNeill AD, Bansal-Travers M, Fix BV, et al. (2013) Effectiveness of stop-smoking medications: findings from the International Tobacco Control (ITC) four country survey. Addiction 108:193–202PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, et al. (2006) Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56–63PubMedCrossRefGoogle Scholar
  7. 7.
    Koegelenberg CF, Noor F, Bateman ED, van Zyl-Smit RN, Bruning A, O’Brien JA, et al. (2014) Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA 312:155–161PubMedCrossRefGoogle Scholar
  8. 8.
    Espanol E, Kelsberg G, Safranek S (2014) Clinical inquiry: does any antidepressant besides bupropion help smokers quit? J Fam Pract 63:680–688PubMedGoogle Scholar
  9. 9.
    Verde Z, Santiago C, Rodriguez Gonzalez-Moro JM, de Lucas Ramos P, Lopez Martin S, Bandres F, et al. ‘Smoking genes’: a genetic association study. PLoS One 2011;6:e26668.Google Scholar
  10. 10.
    Broms U, Silventoinen K, Madden PA, Heath AC, Kaprio J (2006) Genetic architecture of smoking behavior: a study of Finnish adult twins. Twin Res Hum Genet 9:64–72PubMedCrossRefGoogle Scholar
  11. 11.
    Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, Bucholz KK, et al. (2004) Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med 34:865–879PubMedCrossRefGoogle Scholar
  12. 12.
    Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF, et al. (2007) Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 16:24–35PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, et al. (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16:36–49PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Lerman CE, Schnoll RA, Munafo MR (2007) Genetics and smoking cessation improving outcomes in smokers at risk. Am J Prev Med 33:S398–S405PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Xian H, Scherrer JF, Madden PA, Lyons MJ, Tsuang M, True WR, et al. (2003) The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine Tob Res 5:245–254PubMedCrossRefGoogle Scholar
  16. 16.
    Lerman C, Shields PG, Wileyto EP, Audrain J, Pinto A, Hawk L, et al. (2002) Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics 12:627–634PubMedCrossRefGoogle Scholar
  17. 17.
    David SP, Brown RA, Papandonatos GD, Kahler CW, Lloyd-Richardson EE, Munafo MR, et al. (2007) Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation. Nicotine Tob Res 9:821–833PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    David SP, Niaura R, Papandonatos GD, Shadel WG, Burkholder GJ, Britt DM, et al. (2003) Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome? Nicotine Tob Res 5:935–942PubMedCrossRefGoogle Scholar
  19. 19.
    Han DH, Joe KH, Na C, Lee YS (2008) Effect of genetic polymorphisms on smoking cessation: a trial of bupropion in Korean male smokers. Psychiatr Genet 18:11–16PubMedCrossRefGoogle Scholar
  20. 20.
    Dubertret C, Gouya L, Hanoun N, Deybach JC, Ades J, Hamon M, et al. (2004) The 3′ region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. Schizophr Res 67:75–85PubMedCrossRefGoogle Scholar
  21. 21.
    Neville MJ, Johnstone EC, Walton RT (2004) Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 23:540–545PubMedCrossRefGoogle Scholar
  22. 22.
    Arenaz I, Vicente J, Fanlo A, Vasquez P, Medina JC, Conde B, et al. (2010) Haplotype structure and allele frequencies of CYP2B6 in Spaniards and Central Americans. Fundam Clin Pharmacol 24:247–253PubMedGoogle Scholar
  23. 23.
    Issa JS, Abe TO, Moura S, Santos PC, Pereira AC (2013) Effectiveness of coadministration of varenicline, bupropion, and serotonin reuptake inhibitors in a smoking cessation program in the real-life setting. Nicotine Tob Res 15:1146–1150PubMedCrossRefGoogle Scholar
  24. 24.
    Issa JS, Santos PC, Vieira LP, Abe TO, Kuperszmidt CS, Nakasato M, et al. (2014) Smoking cessation and weight gain in patients with cardiovascular disease or risk factor. Int J Cardiol 172:485–487PubMedCrossRefGoogle Scholar
  25. 25.
    Fagerstrom KO, Heatherton TF, Kozlowski LT (1990) Nicotine addiction and its assessment. Ear Nose Throat J 69:763–765PubMedGoogle Scholar
  26. 26.
    Santos PC, Soares RA, Santos DB, Nascimento RM, Coelho GL, Nicolau JC, et al. (2011) CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. BMC Med Genet 12:13PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Santos PC, Soares RA, Nascimento RM, Machado-Coelho GL, Mill JG, Krieger JE, et al. (2011) SLCO1B1 rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group. BMC Med Genet 12:136PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U, et al. (2001) Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11:399–415PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang H, Sridar C, Kenaan C, Amunugama H, Ballou DP, Hollenberg PF (2011) Polymorphic variants of cytochrome P450 2B6 (CYP2B6.4-CYP2B6.9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6.8) impairs formation of a functional cytochrome p450-reductase complex. J Pharmacol Exp Ther 338:803–809PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Lerman C, Shields PG, Wileyto EP, Audrain J, Hawk Jr. LH, Pinto A, et al. (2003) Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Health Psychol 22:541–548PubMedCrossRefGoogle Scholar
  31. 31.
    Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, et al. (2000) CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 28:1176–1183PubMedGoogle Scholar
  32. 32.
    Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, et al. (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222–1230PubMedGoogle Scholar
  33. 33.
    Zanger UM, Klein K (2013) Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet 4:24PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Kirchheiner J, Klein C, Meineke I, Sasse J, Zanger UM, Murdter TE, et al. (2003) Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 13:619–626PubMedCrossRefGoogle Scholar
  35. 35.
    Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, et al. (2012) CYP2B6 and bupropion’s smoking-cessation pharmacology: the role of hydroxybupropion. Clin Pharmacol Ther 92:771–777PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Telenti A, Zanger UM (2008) Pharmacogenetics of anti-HIV drugs. Annu Rev Pharmacol Toxicol 48:227–256PubMedCrossRefGoogle Scholar
  37. 37.
    Rakhmanina NY, van den Anker JN (2010) Efavirenz in the therapy of HIV infection. Expert Opin Drug Metab Toxicol 6:95–103PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M, et al. (2008) Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther 325:284–292PubMedCrossRefGoogle Scholar
  39. 39.
    Nyakutira C, Roshammar D, Chigutsa E, Chonzi P, Ashton M, Nhachi C, et al. (2008) High prevalence of the CYP2B6 516G–>T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol 64:357–365PubMedCrossRefGoogle Scholar
  40. 40.
    Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, et al. (2004) Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 14:225–238PubMedCrossRefGoogle Scholar
  41. 41.
    Bierut LJ, Rice JP, Edenberg HJ, Goate A, Foroud T, Cloninger CR, et al. (2000) Family-based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking. Am J Med Genet 90:299–302PubMedCrossRefGoogle Scholar
  42. 42.
    Singleton AB, Thomson JH, Morris CM, Court JA, Lloyd S, Cholerton S (1998) Lack of association between the dopamine D2 receptor gene allele DRD2*A1 and cigarette smoking in a United Kingdom population. Pharmacogenetics 8:125–128PubMedCrossRefGoogle Scholar
  43. 43.
    Johnstone EC, Yudkin P, Griffiths SE, Fuller A, Murphy M, Walton R (2004) The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population. Addict Biol 9:221–226PubMedCrossRefGoogle Scholar
  44. 44.
    Riccardi LN, Carano F, Bini C, Ceccardi S, Ferri G, Pelotti S. CYP2B6 gene single-nucleotide polymorphisms in an Italian population sample and relationship with nicotine dependence. Genet Test Mol Biomarkers; 2015.Google Scholar
  45. 45.
    Erblich J, Lerman C, Self DW, Diaz GA, Bovbjerg DH (2004) Stress-induced cigarette craving: effects of the DRD2 TaqI RFLP and SLC6A3 VNTR polymorphisms. Pharmacogenomics J 4:102–109PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Paulo Roberto Xavier Tomaz
    • 1
  • Juliana Rocha Santos
    • 1
  • Jaqueline Scholz Issa
    • 2
  • Tânia Ogawa Abe
    • 2
  • Patrícia Viviane Gaya
    • 2
  • José Eduardo Krieger
    • 1
  • Alexandre Costa Pereira
    • 1
    • 3
    Email author
  • Paulo Caleb Júnior Lima Santos
    • 1
    • 3
    Email author
  1. 1.Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor)University of Sao Paulo Medical SchoolSao PauloBrazil
  2. 2.Smoking Cessation Program Department, Heart Institute (InCor)University of Sao Paulo Medical SchoolSao PauloBrazil
  3. 3.Laboratory of Genetics and Molecular Cardiology, Heart InstituteUniversity of Sao Paulo Medical SchoolSão PauloBrazil

Personalised recommendations