Associations of CYP2A6 Gene Polymorphism with Smoking Status Among Jordanians: Gender-Related Differences

Author(s): Hana M. Hammad*, Amer Imraish, Belal Azab, Al M. Best, Yousef S. Khader, Malek Zihlif.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 9 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Cytochrome P450 2A6 enzyme (CYP2A6), an essential hepatic enzyme involved in the metabolism of drugs, is responsible for a major metabolic pathway of nicotine. Variation in the activity of polymorphic CYP2A6 alleles has been implicated in inter-individual differences in nicotine metabolism.

Aims: The objective of the current study was to assess the association between the smoking status and the cytochrome P450 2A6 enzyme (CYP2A6) genotype in Jordanians.

Methods: In the current study, 218 (117 Male and 101 female) healthy unrelated Jordanian volunteers were recruited. CYP2A6*1B, CYP2A6*4 and CYP2A6*9 were determined and correlated with subject smoking status.

Results: *1A/*1A was the most common genetic polymorphism in the overall study population, with no significant frequency differences between smokers and non-smokers. When the population was divided according to gender, only male smokers showed a significant correlation between genotype and smoking status. Considering the CYP2A6*9 genotype, the results showed differences in distribution between smokers and non-smokers, but only women showed a significant association between CYP2A6*9 allele genotype and smoking status.

Conclusion: The results of this study show that there is a significant association between CYP2A6*9 genotype and smoking status. They also show that CYP2A6 genotype is significantly influenced by gender.

Keywords: CYP2A6, polymorphisms, drug metabolism, nicotine, smoking behavior, Jordanians, gender-related differences.

World Health Organization. WHO report on the global tobacco epidemic, 2017: Monitoring tobacco use and prevention policies; WHO: Switzerland, 2017.
Xu, X.; Bishop, E.E.; Kennedy, S.M.; Simpson, S.A.; Pechacek, T.F. Annual healthcare spending attributable to cigarette smoking: An update. Am. J. Prev. Med., 2015, 48(3), 326-333.
[] [PMID: 25498551]
Hitchman, S.C.; Fong, G.T. Gender empowerment and female-to-male smoking prevalence ratios. Bull. World Health Organ., 2011, 89(3), 195-202.
[] [PMID: 21379415]
Oscarson, M. Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: Implications for interindividual differences in nicotine metabolism. Drug Metab. Dispos., 2001, 29(2), 91-95.
[PMID: 11159795]
Nakajima, M.; Yamamoto, T.; Nunoya, K.; Yokoi, T.; Nagashima, K.; Inoue, K.; Funae, Y.; Shimada, N.; Kamataki, T.; Kuroiwa, Y. Characterization of CYP2A6 involved in 3′-hydroxylation of cotinine in human liver microsomes. J. Pharmacol. Exp. Ther., 1996, 277(2), 1010-1015.
[PMID: 8627511]
Kwon, J-T.; Nakajima, M.; Chai, S.; Yom, Y-K.; Kim, H-K.; Yamazaki, H.; Sohn, D-R.; Yamamoto, T.; Kuroiwa, Y.; Yokoi, T. Nicotine metabolism and CYP2A6 allele frequencies in Koreans. Pharmacogenetics, 2001, 11(4), 317-323.
[] [PMID: 11434509]
Yoshida, R.; Nakajima, M.; Watanabe, Y.; Kwon, J.T.; Yokoi, T. Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br. J. Clin. Pharmacol., 2002, 54(5), 511-517.
[] [PMID: 12445030]
Nakajima, M.; Fukami, T.; Yamanaka, H.; Higashi, E.; Sakai, H.; Yoshida, R.; Kwon, J.T.; McLeod, H.L.; Yokoi, T. Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clin. Pharmacol. Ther., 2006, 80(3), 282-297.
[] [PMID: 16952495]
Martins, I. Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries.In: Top 10 Contribution on Genetics; Avid Science: Berlin, Germany, 2018, pp. 1-35.
Mwenifumbo, J.C.; Sellers, E.M.; Tyndale, R.F. Nicotine metabolism and CYP2A6 activity in a population of black African descent: Impact of gender and light smoking. Drug Alcohol Depend., 2007, 89(1), 24-33.
[] [PMID: 17161559]
Ingelman-Sundberg, M. Pharmacogenomic biomarkers for prediction of severe adverse drug reactions. N. Engl. J. Med., 2008, 358, 637-639.
Tyndale, R.F.; Sellers, E.M. Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Ther. Drug Monit., 2002, 24(1), 163-171.
[] [PMID: 11805739]
Hukkanen, J.; Jacob, P., III; Benowitz, N.L. Metabolism and disposition kinetics of nicotine. Pharmacol. Rev., 2005, 57(1), 79-115.
[] [PMID: 15734728]
Johnstone, E.; Benowitz, N.; Cargill, A.; Jacob, R.; Hinks, L.; Day, I.; Murphy, M.; Walton, R. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin. Pharmacol. Ther., 2006, 80(4), 319-330.
[] [PMID: 17015050]
Raunio, H.; Rautio, A.; Gullstén, H.; Pelkonen, O. Polymorphisms of CYP2A6 and its practical consequences. Br. J. Clin. Pharmacol., 2001, 52(4), 357-363.
[] [PMID: 11678779]
Mwenifumbo, J.C.; Lessov-Schlaggar, C.N.; Zhou, Q.; Krasnow, R.E.; Swan, G.E.; Benowitz, N.L.; Tyndale, R.F. Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism. Clin. Pharmacol. Ther., 2008, 83(1), 115-121.
[] [PMID: 17522595]
Malaiyandi, V.; Lerman, C.; Benowitz, N.L.; Jepson, C.; Patterson, F.; Tyndale, R.F. Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy. Mol. Psychiatry, 2006, 11(4), 400-409.
[] [PMID: 16402128]
Liu, T.; David, S.P.; Tyndale, R.F.; Wang, H.; Zhou, Q.; Ding, P.; He, Y.H.; Yu, X.Q.; Chen, W.; Crump, C.; Wen, X.Z.; Chen, W.Q. Associations of CYP2A6 genotype with smoking behaviors in southern China. Addiction, 2011, 106(5), 985-994.
[] [PMID: 21205058]
Yasuda, S.U.; Zhang, L.; Huang, S.M. The role of ethnicity in variability in response to drugs: Focus on clinical pharmacology studies. Clin. Pharmacol. Ther., 2008, 84(3), 417-423.
[] [PMID: 18615002]
Zihlif, M.; Imraish, A.; Irshaid, Y.M. Frequency of certain single-nucleotide polymorphisms and duplication of CYP2D6 in the Jordanian population. Genet. Test. Mol. Biomarkers, 2012, 16(10), 1201-1205.
[] [PMID: 22905959]
He, L-N.; Yang, A-H.; Cui, T-Y.; Zhai, Y-R.; Zhang, F-L.; Chen, J-X.; Jin, C-H.; Fan, Y-W.; Wu, Z-J.; Wang, L-L.; He, X. Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity. Xenobiotica, 2015, 45(4), 361-372.
[] [PMID: 25815638]
Fukami, T.; Nakajima, M.; Yamanaka, H.; Fukushima, Y.; McLeod, H.L.; Yokoi, T. A novel duplication type of CYP2A6 gene in African-American population. Drug Metab. Dispos., 2007, 35(4), 515-520.
[] [PMID: 17267622]
Yuan, J-M.; Nelson, H.H.; Carmella, S.G.; Wang, R.; Kuriger-Laber, J.; Jin, A.; Adams-Haduch, J.; Hecht, S.S.; Koh, W-P.; Murphy, S.E. CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese health study. Carcinogenesis, 2017, 38(4), 411-418.
[] [PMID: 28182203]
Tyndale, R.F.; Sellers, E.M. Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk. Drug Metab. Dispos., 2001, 29(4 Pt 2), 548-552.
[PMID: 11259349]
Ray, R.; Tyndale, R.F.; Lerman, C. Nicotine dependence pharmacogenetics: Role of genetic variation in nicotine-metabolizing enzymes. J. Neurogenet., 2009, 23(3), 252-261.
[] [PMID: 19169923]
O’Loughlin, J.; Paradis, G.; Kim, W.; DiFranza, J.; Meshefedjian, G.; McMillan-Davey, E.; Wong, S.; Hanley, J.; Tyndale, R.F. Genetically decreased CYP2A6 and the risk of tobacco dependence: A prospective study of novice smokers. Tob. Control, 2004, 13(4), 422-428.
[] [PMID: 15564629]
Audrain-McGovern, J.; Al Koudsi, N.; Rodriguez, D.; Wileyto, E.P.; Shields, P.G.; Tyndale, R.F. The role of CYP2A6 in the emergence of nicotine dependence in adolescents. Pediatrics, 2007, 119(1), e264-e274.
[] [PMID: 17130279]
Al Koudsi, N.; Hoffmann, E.B.; Assadzadeh, A.; Tyndale, R.F. Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors. Eur. J. Clin. Pharmacol., 2010, 66(3), 239-251.
[] [PMID: 20012030]
Messina, E.S.; Tyndale, R.F.; Sellers, E.M. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J. Pharmacol. Exp. Ther., 1997, 282(3), 1608-1614.
[PMID: 9316878]
Hadidi, H.; Irshaid, Y.; Vågbø, C.B.; Brunsvik, A.; Cholerton, S.; Zahlsen, K.; Idle, J.R. Variability of coumarin 7- and 3-hydroxylation in a Jordanian population is suggestive of a functional polymorphism in cytochrome P450 CYP2A6. Eur. J. Clin. Pharmacol., 1998, 54(5), 437-441.
[] [PMID: 9754990]
Oscarson, M.; McLellan, R.A.; Gullstén, H.; Yue, Q-Y.; Lang, M.A.; Bernal, M.L.; Sinues, B.; Hirvonen, A.; Raunio, H.; Pelkonen, O.; Ingelman-Sundberg, M. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett., 1999, 448(1), 105-110.
[] [PMID: 10217419]
Schoedel, K.A.; Hoffmann, E.B.; Rao, Y.; Sellers, E.M.; Tyndale, R.F. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics, 2004, 14(9), 615-626.
[] [PMID: 15475735]
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(2), 455-460.
[] [PMID: 11394901]
Yoshida, R.; Nakajima, M.; Nishimura, K.; Tokudome, S.; Kwon, J.T.; 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(1), 69-76.
[] [PMID: 12844137]
Emamghoreishi, M.; Bokaee, H-R.; Keshavarz, M. CYP2A6 genetic polymorphism and its relation to risk of smoking dependence in male Iranians. Physiol. Pharmacol., 2009, 12(4), 296-306.
Djordjevic, N.; Carrillo, J.A.; Gervasini, G.; Jankovic, S.; Aklillu, E. In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population. Eur. J. Clin. Pharmacol., 2010, 66(6), 571-578.
[] [PMID: 20155256]
Higashi, E.; Fukami, T.; Itoh, M.; Kyo, S.; Inoue, M.; Yokoi, T.; Nakajima, M. Human CYP2A6 is induced by estrogen via estrogen receptor. Drug Metab. Dispos., 2007, 35(10), 1935-1941.
[] [PMID: 17646279]
Benowitz, N.L.; Hatsukami, D. Gender differences in the pharmacology of nicotine addiction. Addict. Biol., 1998, 3(4), 383-404.
[] [PMID: 26735114]
Benowitz, N.L.; Jacob, P., III Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J. Pharmacol. Exp. Ther., 1985, 234(1), 153-155.
[PMID: 4009497]
Dempsey, D.; Jacob, P., III; Benowitz, N.L. Accelerated metabolism of nicotine and cotinine in pregnant smokers. J. Pharmacol. Exp. Ther., 2002, 301(2), 594-598.
[] [PMID: 11961061]
Benowitz, N.L.; Swan, G.E.; Jacob, P., III; Lessov-Schlaggar, C.N.; Tyndale, R.F. CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin. Pharmacol. Ther., 2006, 80(5), 457-467.
[] [PMID: 17112802]
Zeman, M.V.; Hiraki, L.; Sellers, E.M. Gender differences in tobacco smoking: Higher relative exposure to smoke than nicotine in women. J. Womens Health Gend. Based Med., 2002, 11(2), 147-153.
[] [PMID: 11975862]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [765 - 770]
Pages: 6
DOI: 10.2174/1389200220666190827161112
Price: $65

Article Metrics

PDF: 35
PRC: 1