CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation (original) (raw)

The Pharmacogenomics Journal volume 6, pages 115–119 (2006)Cite this article

Abstract

CYP2A6 is the main enzyme that catalyzes nicotine into cotinine. Interindividual differences in nicotine metabolism result at least partially from polymorphic variation of CYP2A6 gene. In this study, we evaluated the influence of CYP2A6 polymorphisms on clinical phenotypes of smoking, such as smoking habit and withdrawal symptoms. Japanese smokers (_n_=107) were genotyped for CYP2A6*1, *4 and *9. Consistent with the previous reports, CYP2A6 genotypes have a tendency to correlate with the number of cigarettes per day and with daily intake of nicotine. Interestingly, CYP2A6 high-activity group (CYP2A6*1/*1, *1/*9, *1/*4, *9/*9) smoked the first cigarette of the day earlier than low-activity group (CYP2A6*4/*9, *4/*4), indicating more remarkable nicotine dependence. Furthermore, nicotine withdrawal symptoms were more serious in smoking cessation in CYP2A6 high-activity group. Collectively, CYP2A6 genotypes are related with nicotine dependence, influencing smoking habits and withdrawal symptoms in quitting smoking. It is proposed that individualized smoking cessation program could be designed based on CYP2A6 genotypes.

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References

  1. Benowitz NL, Jacob III P . Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 1994; 56: 483–493.
    Article CAS Google Scholar
  2. Nunoya K, Yokoi T, Kimura K, Inoue K, Kodama T, Funayama et al. A new deleted allele in the human cytochrome _P_450 2A6 (CYP2A6) gene found in individuals showing poor metabolic capacity to coumarin and (+)-_cis_-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502). Pharmacogenetics 1998; 8: 239–249.
    Article CAS Google Scholar
  3. Nunoya KI, Yokoi T, Kimura K, Kainuma T, Satoh K, Kinoshita M et al. A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-_cis_-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans. J Pharmacol Exp Ther 1999; 289: 437–442.
    CAS PubMed Google Scholar
  4. Pitarque M, von Richter O, Oke B, Berkkan H, Oscarson M, Ingelman-Sundberg M . Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochem Biophys Res Commun 2001; 284: 455–460.
    Article CAS Google Scholar
  5. Yoshida R, Nakajima M, Nishimura K, Tokudome S, Kwon JT, Yokoi T . Effects of polymorphism in promoter region of human CYP2A6 gene (CYP2A6*9) on expression level of messenger ribonucleic acid and enzymatic activity in vivo and in vitro. Clin Pharmacol Ther 2003; 74: 69–76.
    Article CAS Google Scholar
  6. Kiyotani K, Yamazaki H, Fujieda M, Iwano S, Matsumura K, Satarug S et al. Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9). Pharmacogenetics 2003; 13: 689–695.
    Article CAS Google Scholar
  7. Jarvik ME, Madsen DC, Olmstead RE, Iwamoto-Schaap PN, Elins JL, Benowitz NL . Nicotine blood levels and subjective craving for cigarettes. Pharmacol Biochem Behav 2000; 66: 553–558.
    Article CAS Google Scholar
  8. Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis 2004; 25: 2451–2458.
    Article CAS Google Scholar
  9. Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF . Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 2004; 14: 615–626.
    Article CAS Google Scholar
  10. Minematsu N, Nakamura H, Iwata M, Tateno H, Nakajima T, Takahashi S et al. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema. Thorax 2003; 58: 623–628.
    Article CAS Google Scholar
  11. Ando M, Hamajima N, Ariyoshi N, Kamataki T, Matsuo K, Ohno Y . Association of CYP2A6 gene deletion with cigarette smoking status in Japanese adults. J Epidemiol 2003; 13: 176–181.
    Article Google Scholar
  12. Yang M, Kunugita N, Kitagawa K, Tateno H, Nakajima T, Takahashi S et al. Individual differences in urinary cotinine levels in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes. Cancer Epidemiol Biomarkers Prev 2001; 10: 589–593.
    CAS PubMed Google Scholar
  13. Zhang X, Amemo K, Ameno S, Iwahashi K, Kinoshita H, Kubota T et al. Lack of association between smoking and CYP2A6 gene polymorphisms in a Japanese population. Nihon Arukoru Yakubutsu Igakkai Zasshi 2001; 36: 486–490.
    CAS PubMed Google Scholar
  14. Tan W, Chen GF, Xing DY, Song CY, Kadlubar FF, Lin DX . Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population. Int J Cancer 2001; 95: 96–101.
    Article CAS Google Scholar
  15. Loriot MA, Rebuissou S, Oscarson M, Cenee S, Miyamoto M, Ariyoshi N et al. Genetic polymorphisms of cytochrome _P_450 2A6 in a case–control study on lung cancer in a French population. Pharmacogenetics 2001; 11: 39–44.
    Article CAS Google Scholar
  16. John U, Meyer C, Schumann A, Hapke U, Rumpf HJ, Adam C et al. A short form of the Fagerstrom Test for Nicotine Dependence and the Heaviness of Smoking Index in two adult population samples. Addict Behav 2004; 29: 1207–1212.
    Article CAS Google Scholar
  17. Dani JA, Heinemann S et al. Molecular and cellular aspects of nicotine abuse. Neuron 1996; 16: 905–908.
    Article CAS Google Scholar
  18. Ariyoshi N, Takahashi Y, Miyamoto M et al. Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C. Pharmacogenetics 2000; 10: 687–693.
    Article CAS Google Scholar

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Acknowledgements

We thank Ms Y Murao for her excellent secretary work. This work is supported by a Grant-in-Aid for Scientific Research from Ministry of Education, Science, Sports and Culture of Japan.

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Author notes

  1. T Kubota and C Nakajima-Taniguchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita City, Osaka, Japan
    T Kubota, T Fukuda, M Maeda, E Tange, R Ueki, K Kawashima, Y Fujio & J Azuma
  2. Osaka Regional Taxation Bureau's Clinic, Otemae, Chuo-ku, 540-0008, Osaka, Japan
    C Nakajima-Taniguchi & H Hara
  3. Funamoto Clinic, Urakaze-cho, Koshien, Nishinomiya City, 663-8165, Hyogo, Japan
    M Funamoto

Authors

  1. T Kubota
  2. C Nakajima-Taniguchi
  3. T Fukuda
  4. M Funamoto
  5. M Maeda
  6. E Tange
  7. R Ueki
  8. K Kawashima
  9. H Hara
  10. Y Fujio
  11. J Azuma

Corresponding author

Correspondence toJ Azuma.

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Kubota, T., Nakajima-Taniguchi, C., Fukuda, T. et al. CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation.Pharmacogenomics J 6, 115–119 (2006). https://doi.org/10.1038/sj.tpj.6500348

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