Cytochrome P450 2A6 and 2B6 polymorphisms and smoking cessation success in patients treated with varenicline

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



The identification of variants in genes involved in nicotine metabolism may have implications for the pharmacological therapy of smoking. In the scenario of precision medicine, the aim of this study was to evaluate a possible association of cytochrome P450 2A6 and 2B6 polymorphisms with varenicline pharmacotherapy.


The present study included 167 patients treated with varenicline in monotherapy who were from a cohort study of 1049 patients (treated with smoking cessation drugs: nicotine replacement therapy, bupropion, varenicline, or combinations of same). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. The CYP2A6 rs1801272 and rs28399433 and CYP2B6 rs8109525 polymorphisms were genotyped by real-time PCR using the TaqMan® platform.


Patients with AG or GG genotypes for CYP2B6 rs8109525 had a higher success rate of smoking cessation with varenicline (51.2%) compared with carriers of the AA genotypes (33.3%, P = 0.03, n = 167). The AG or GG genotypes were also associated with a higher odds ratio of success, even in a multivariate analysis adjusting for potential confounders (OR = 2.01; 95%CI = 1.01 to 4.00; P = 0.047).


CYP2B6 rs8109525 was associated with a higher success rate of smoking cessation with varenicline treatment. This finding may be useful in pharmacogenomic strategies for smoking cessation therapy.


CYP2A6 CYP2B6 Nicotine metabolism Smoking cessation Polymorphism rs8109525 



We thank the patients who participated in the study and the technical assistance of the Laboratory of Genetics and Molecular Cardiology group.

Authorship and author responsibilities

PRXT, MK, JRS, and PCJLS carried out the molecular genetic and statistical analysis and drafted the manuscript. PCJLS, JS, TOA, PVG, JEK, and ACP participated in the design of the study and ceded the facilities. JS, TOA, and PVG selected the patients. All authors contributed critically to the manuscript, whose present version was read and approved by all.

Funding disclosure

We thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo, Brazil)—Proc. 2013/09295-3 and CNPq (Proc. 470410/2013-2), Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001 (PRX Tomaz and JR Santos are recipients of fellowships from CAPES, Brazil). Sociedade Hospital Samaritano—Ministério da Saúde (PROADI-SUS; SIPAR: 25000.180.672/2011-81).

Compliance with ethical standards

Written informed consent was obtained from all participants prior to entering the study (CAPPESQ no. 0022/11—SDC: 3579/10/168).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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  1. 1.
    ORGANIZATION WH (2015) WHO Report on the global tobacco epidemic, 2015. Raising taxes on tobaccoGoogle Scholar
  2. 2.
    Ribeiro SA, Jardim JR, Laranjeira RR, Alves AK, Kesselring F, Fleissig L, Almeida MZ, Matsuda M, Hamamoto RS (1999) Smoking prevalence at the Federal University of São Paulo, 1996--preliminary data of an institutional program. Rev Assoc Med Bras (1992) 45:39–44CrossRefGoogle Scholar
  3. 3.
    Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O, Swan GE, Goate AM, Rutter J, Bertelsen S, Fox L, Fugman D, Martin NG, Montgomery GW, Wang JC, Ballinger DG, Rice JP, Bierut LJ (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16:36–49CrossRefGoogle Scholar
  4. 4.
    Sarginson JE, Killen JD, Lazzeroni LC, Fortmann SP, Ryan HS, Schatzberg AF, Murphy GM (2011;156B) Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy. Am J Med Genet B Neuropsychiatr Genet 156:275–284CrossRefGoogle Scholar
  5. 5.
    Marinho IM, Carmona MJC, Benseñor FEM, Hertel JM, Moraes MFB, Santos PCJL, Vane MF, Issa JS (2018) Surgery is unlikely to be enough for a patient to stop smoking 24h prior to hospital admission. Rev Bras Anestesiol 68:344–350CrossRefGoogle Scholar
  6. 6.
    Henningfield JE, Slade J (1998) Tobacco-dependence medications: public health and regulatory issues. Food Drug Law J 53(suppl):75–114Google Scholar
  7. 7.
    Laviolette SR, van der Kooy D (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5:55–65CrossRefGoogle Scholar
  8. 8.
    Fiore MCB, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER et al (2000) Treating tobacco use and dependence. In: Clinical Practice GuidelineGoogle Scholar
  9. 9.
    Fiore MCJ, Baker TB, Bailey WC, Benowitz NL, Curry SJ et al (2008) Treating tobacco use and dependence: 2008 update. In: Clinical Practice GuidelineGoogle Scholar
  10. 10.
    Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295:321–327Google Scholar
  11. 11.
    Sieminska A, Jassem E, Kita-Milczarska K (2015) Nicotine dependence in an isolated population of Kashubians from North Poland: a population survey. BMC Public Health 15:80CrossRefGoogle Scholar
  12. 12.
    Ho MK, Tyndale RF (2007) Overview of the pharmacogenomics of cigarette smoking. Pharmacogenomics J 7:81–98CrossRefGoogle Scholar
  13. 13.
    Silva AP, Scholz J, Abe TO, Pinheiro GG, Gaya PV, Pereira AC, Santos PC (2016) Influence of smoking cessation drugs on blood pressure and heart rate in patients with cardiovascular disease or high risk score: real life setting. BMC Cardiovasc Disord 16:2CrossRefGoogle Scholar
  14. 14.
    Scholz J, Santos PC, Buzo CG, Lopes NH, Abe TO, Gaya PV, Pierri H, Amorim C, Pereira AC (2016) Effects of aging on the effectiveness of smoking cessation medication. Oncotarget. 7:30032–30036CrossRefGoogle Scholar
  15. 15.
    Hiroi N, Scott D (2009) Constitutional mechanisms of vulnerability and resilience to nicotine dependence. Mol Psychiatry 14:653–667CrossRefGoogle Scholar
  16. 16.
    Volkow ND (2005) What do we know about drug addiction? Am J Psychiatry 162:1401–1402CrossRefGoogle Scholar
  17. 17.
    Tomaz PR, Santos JR, Issa JS, Abe TO, Gaya PV, Krieger JE, Pereira AC, Santos PC (2015) CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy. Eur J Clin Pharmacol 71:1067–1073CrossRefGoogle Scholar
  18. 18.
    Chatkin JM (2006) The influence of genetics on nicotine dependence and the role of pharmacogenetics in treating the smoking habit. J Bras Pneumol 32:573–579CrossRefGoogle Scholar
  19. 19.
    Bibi Z (2008) Role of cytochrome P450 in drug interactions. Nutr Metab (Lond) 5:27CrossRefGoogle Scholar
  20. 20.
    King DP, Paciga S, Pickering E, Benowitz NL, Bierut LJ, Conti DV, Kaprio J, Lerman C, Park PW (2012) Smoking cessation pharmacogenetics: analysis of varenicline and bupropion in placebo-controlled clinical trials. Neuropsychopharmacology 37:641–650CrossRefGoogle Scholar
  21. 21.
    Tomaz PRX, Santos JR, Scholz J, Abe TO, Gaya PV, Negrão AB, Krieger JE, Pereira AC, Santos PCJL (2018) Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women. BMC Med Genet 19:55CrossRefGoogle Scholar
  22. 22.
    Pérez-Rubio G, López-Flores LA, Ramírez-Venegas A, Noé-Díaz V, García-Gómez L, Ambrocio-Ortiz E, Sánchez-Romero C, Hernández-Zenteno RJ, Sansores RH, Falfán-Valencia R (2017) Genetic polymorphisms in CYP2A6 are associated with a risk of cigarette smoking and predispose to smoking at younger ages. Gene. 628:205–210CrossRefGoogle Scholar
  23. 23.
    López-Flores LA, Pérez-Rubio G, Ramírez-Venegas A, Ambrocio-Ortiz E, Sansores RH, Falfán-Valencia R (2017) Data on polymorphisms in CYP2A6 associated to risk and predispose to smoking related variables. Data Brief 15:86–91CrossRefGoogle Scholar
  24. 24.
    Allenby CE, Boylan KA, Lerman C, Falcone M (2016) Precision medicine for tobacco dependence: development and validation of the nicotine metabolite ratio. J NeuroImmune Pharmacol 11:471–483CrossRefGoogle Scholar
  25. 25.
    Bloom AJ, Martinez M, Chen LS, Bierut LJ, Murphy SE, Goate A (2013) CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes. PLoS One 8:e79700CrossRefGoogle Scholar
  26. 26.
    Chenoweth MJ, Tyndale RF (2017) Pharmacogenetic optimization of smoking cessation treatment. Trends Pharmacol Sci 38:55–66CrossRefGoogle Scholar
  27. 27.
    Bloom AJ, Wang PF, Kharasch ED (2019) Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes. Pharmacol Res Perspect 7:e00468CrossRefGoogle Scholar
  28. 28.
    Tang DW, Hello B, Mroziewicz M, Fellows LK, Tyndale RF, Dagher A (2012) Genetic variation in CYP2A6 predicts neural reactivity to smoking cues as measured using fMRI. Neuroimage. 60:2136–2143CrossRefGoogle Scholar
  29. 29.
    Sofuoglu M, Herman AI, Nadim H, Jatlow P (2012) Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology. 37:1509–1516CrossRefGoogle Scholar
  30. 30.
    Lerman C, Schnoll RA, Hawk LW, Cinciripini P, George TP, Wileyto EP, Swan GE, Benowitz NL, Heitjan DF, Tyndale RF, Group P-PR (2015) Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med 3:131–138CrossRefGoogle Scholar
  31. 31.
    Issa JS, Abe T, 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 15:1146–1150CrossRefGoogle Scholar
  32. 32.
    Issa JS, Santos PC, Vieira LP, Abe TO, Kuperszmidt CS, Nakasato M, Cardoso E, Amorim C, Pereira AC (2014) Smoking cessation and weight gain in patients with cardiovascular disease or risk factor. Int J Cardiol 172:485–487CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Paulo Roberto Xavier Tomaz
    • 1
  • Mariana Soares Kajita
    • 2
  • Juliana Rocha Santos
    • 1
  • Jaqueline Scholz
    • 3
  • Tânia Ogawa Abe
    • 3
  • Patrícia Viviane Gaya
    • 3
  • José Eduardo Krieger
    • 1
  • Alexandre Costa Pereira
    • 1
  • Paulo Caleb Júnior Lima Santos
    • 2
    Email author
  1. 1.Laboratory of Genetics and Molecular Cardiology, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de MedicinaUniversidade de Sao PauloSao PauloBrazil
  2. 2.Department of Pharmacology—Escola Paulista de MedicinaUniversidade Federal de Sao Paulo EPM-UnifespSão PauloBrazil
  3. 3.Smoking Cessation Program Department, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de MedicinaUniversidade de Sao PauloSao PauloBrazil

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