Genetic Variability in CYP2A6 and the Pharmacokinetics of Nicotine

• Henningfield JE , MiyasatoK, JasinskiDR: Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine.J. Pharmacol. Exp. Ther.234(1), 1–12 (1985).
   PubMed Web of Science ®Google Scholar
• US Department of Health, Education, and Welfare: Smoking And Health. Report Of The Advisory Committee to the Surgeon General Of The Public Health Service. In: PHS Publ. No. 1103. USDHEW, Washington, DC, USA (1964).
   Google Scholar
• Schneider NG , PopekP, JarvikME, Gritz ER: The use of nicotine gum during cessation of smoking. Am. J. Psychiatry134(4), 439–440 (1977).
   PubMed Web of Science ®Google Scholar
• Puska P , BjorkqvistS, KoskelaK: Nicotine-containing chewing gum in smoking cessation: a double blind trial with half year follow-up.Addict. Behav.4(2), 141–146 (1979).
   PubMed Web of Science ®Google Scholar
• Levin ED , ConnersCK, SparrowE et al.: Nicotine effects on adults with attention-deficit/hyperactivity disorder.Psychopharmacology (Berl.)123(1), 55–63 (1996).
   PubMed Web of Science ®Google Scholar
• Potter AS , NewhousePA: Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyperactivity disorder.Psychopharmacology (Berl.)176(2), 182–194 (2004).
   PubMed Web of Science ®Google Scholar
• Engeland C , MahoneyC, MohrE, Ilivitsky V, Knott VJ: Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer‘s disease: an event-related potential study. Pharmacol. Biochem. Behav.72(1–2), 457–464 (2002).
   PubMed Web of Science ®Google Scholar
• White HK , LevinED: Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment.Psychopharmacology (Berl.)171(4), 465–471 (2004).
   PubMed Web of Science ®Google Scholar
• Vieregge A , SiebererM, JacobsH, Hagenah JM, Vieregge P: Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study. Neurology57(6), 1032–1035 (2001).
   PubMed Web of Science ®Google Scholar
• Lemay S , ChouinardS, BlanchetP et al.: Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson‘s disease.Prog. Neuropsychopharmacol. Biol. Psychiatry28(1), 31–39 (2004).
   PubMed Web of Science ®Google Scholar
• Orth M , AmannB, RobertsonMM, RothwellJC: Excitability of motor cortex inhibitory circuits in Tourette syndrome before and after single dose nicotine.Brain128(Pt 6), 1292–1300 (2005).
   PubMed Web of Science ®Google Scholar
• Howson AL , BatthS, IlivitskyV et al.: Clinical and attentional effects of acute nicotine treatment in Tourette‘s syndrome.Eur. Psychiatry19(2), 102–112 (2004).
   PubMed Web of Science ®Google Scholar
• Ingram JR , RhodesJ, EvansBK, Thomas GA: Preliminary observations of oral nicotine therapy for inflammatory bowel disease: an open-label Phase I–II study of tolerance. Inflamm. Bowel Dis.11(12), 1092–1096 (2005).
   PubMed Web of Science ®Google Scholar
• McGrath J , McDonaldJW, MacdonaldJK: Transdermal nicotine for induction of remission in ulcerative colitis.Cochrane Database Syst. Rev.CD004722 (2004).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , JacobP 3rd: Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin. Pharmacol. Ther.56(5), 483–493 (1994).
   PubMed Web of Science ®Google Scholar
• Messina ES , TyndaleRF, SellersEM: A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes.J. Pharmacol. Exp. Ther.282(3), 1608–1614 (1997).
   PubMed Web of Science ®Google Scholar
• Nakajima M , YamamotoT, NunoyaK et al.: Role of human cytochrome P4502A6 in C-oxidation of nicotine.Drug Metab. Dispos.24(11), 1212–1217 (1996).
   PubMed Web of Science ®Google Scholar
• Yamano S , TatsunoJ, GonzalezFJ: The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes.Biochemistry29(5), 1322–1329 (1990).
   PubMed Web of Science ®Google Scholar
• Nakajima M , YamamotoT, NunoyaK et al.: Characterization of CYP2A6 involved in 3´-hydroxylation of cotinine in human liver microsomes.J. Pharmacol. Exp. Ther.277(2), 1010–1015 (1996).
   PubMed Web of Science ®Google Scholar
• Hoffman SM , NelsonDR, KeeneyDS: Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19.Pharmacogenetics11(8), 687–698 (2001).
   PubMedGoogle Scholar
• Fernandez-Salguero P , HoffmanSM, CholertonS et al.: A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles.Am. J. Hum. Genet.57(3), 651–660 (1995).
   PubMed Web of Science ®Google Scholar
• Solus JF , AriettaBJ, HarrisJR et al.: Genetic variation in eleven Phase I drug metabolism genes in an ethnically diverse population.Pharmacogenomics5(7), 895–931 (2004).
   PubMed Web of Science ®Google Scholar
• Kiyotani K , FujiedaM, YamazakiH et al.: Twenty one novel single nucleotide polymorphisms (SNPs) of the CYP2A6 gene in Japanese and Caucasians.Drug Metab. Pharmacokinet.17(5), 482–487 (2002).
   PubMedGoogle Scholar
• Haberl M , AnwaldB, KleinK et al.: Three haplotypes associated with CYP2A6 phenotypes in Caucasians.Pharmacogenet. Genomics15(9), 609–624 (2005).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , GriffinC, TyndaleR: Deficient C-oxidation of nicotine continued.Clin. Pharmacol. Ther.70(6), 567 (2001).
   PubMed Web of Science ®Google Scholar
• Kitagawa K , KunugitaN, KatohT, YangM, KawamotoT: The significance of the homozygous CYP2A6 deletion on nicotine metabolism: a new genotyping method of CYP2A6 using a single PCR-RFLP.Biochem. Biophys. Res. Commun.262(1), 146–151 (1999).
   PubMed Web of Science ®Google Scholar
• Xu C , RaoYS, XuB et al.: An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles.Biochem. Biophys. Res. Commun.290(1), 318–324 (2002).
   PubMed Web of Science ®Google Scholar
• Fukami T , NakajimaM, YoshidaR et al.: A novel polymorphism of human CYP2A6 gene CYP2A6*17 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo.Clin. Pharmacol. Ther.76(6), 519–527 (2004).
   PubMed Web of Science ®Google Scholar
• Oscarson M , McLellanRA, GullstenH et al.: Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Lett.460(2), 321–327 (1999).
   PubMed Web of Science ®Google Scholar
• Kitagawa K , KunugitaN, KitagawaM, KawamotoT: CYP2A6*6, a novel polymorphism in cytochrome p450 2A6, has a single amino acid substitution (R128Q) that inactivates enzymatic activity.J. Biol. Chem.276(21), 17830–17835 (2001).
   PubMed Web of Science ®Google Scholar
• Daigo S , TakahashiY, FujiedaM et al.: A novel mutant allele of the CYP2A6 gene (CYP2A6*11) found in a cancer patient who showed poor metabolic phenotype towards tegafur.Pharmacogenetics12(4), 299–306 (2002).
   PubMedGoogle Scholar
• Fukami T , NakajimaM, HigashiE et al.: Characterization of novel CYP2A6 polymorphic alleles (CYP2A6*18 and CYP2A6*19) that affect enzymatic activity.Drug Metab. Dispos.33(8), 1202–1210 (2005).
   PubMed Web of Science ®Google Scholar
• Fukami T , NakajimaM, HigashiE et al.: A novel CYP2A6*20 allele found in African–American population produces a truncated protein lacking enzymatic activity.Biochem. Pharmacol.70(5), 801–808 (2005).
   PubMed Web of Science ®Google Scholar
• Oscarson M , McLellanRA, AspV et al.: Characterization of a novel CYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity.Hum. Mutat.20(4), 275–283 (2002).
   PubMed Web of Science ®Google Scholar
• Pitarque M , von Richter O, Oke B et al.: Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochem. Biophys. Res. Commun.284(2), 455–460 (2001).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , SwanGE, JacobP 3rd, Lessov-Schlaggar CN, Tyndale RF: CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin. Pharmacol. Ther.80(5), 457–467 (2006).
   PubMed Web of Science ®Google Scholar
• Nakajima M , FukamiT, YamanakaH et al.: Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations.Clin. Pharmacol. Ther.80(3), 282–297 (2006).
   PubMed Web of Science ®Google Scholar
• Wang J , PitarqueM, Ingelman-Sundberg M: 3´-UTR polymorphism in the human CYP2A6 gene affects mRNA stability and enzyme expression. Biochem. Biophys. Res. Commun.340(2), 491–497 (2006).
   PubMed Web of Science ®Google Scholar
• Mwenifumbo JC , Lessov-SchlaggarCN, ZhouQ et al.: Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism.Clin. Pharmacol. Ther. (2007) (Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Rao Y , HoffmannE, ZiaM et al.: Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking.Mol. Pharmacol.58(4), 747–755 (2000).
   PubMed Web of Science ®Google Scholar
• Fukami T , NakajimaM, YamanakaH et al.: A novel duplication type of CYP2A6 gene in African–American population.Drug Metab. Dispos.35(4), 515–520 (2007).
   PubMed Web of Science ®Google Scholar
• Mwenifumbo JC , MyersMG, WallTL et al.: Ethnic variation in CYP2A6*7, CYP2A6*8 and CYP2A6*10 as assessed with a novel haplotyping method. Pharmacogenet. Genomics15(3), 189–192 (2005).
   PubMed Web of Science ®Google Scholar
• Al Koudsi N , MwenifumboJC, SellersEM et al.: Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.Eur. J. Clin. Pharmacol.62(6), 481–484 (2006).
   PubMed Web of Science ®Google Scholar
• Pitarque M , von Richter O, Rodriguez-Antona C et al.: A nicotine C-oxidase gene (CYP2A6) polymorphism important for promoter activity. Hum. Mutat.23(3), 258–266 (2004).
   PubMed Web of Science ®Google Scholar
• von Richter O , PitarqueM, Rodriguez-AntonaC et al.: Polymorphic NF-Y dependent regulation of human nicotine C-oxidase (CYP2A6).Pharmacogenetics14(6), 369–379 (2004).
   PubMedGoogle Scholar
• Benowitz NL , Perez-StableEJ, FongI et al.: Ethnic differences in N´-glucuronidation of nicotine and cotinine. J. Pharmacol. Exp. Ther.291(3), 1196–1203 (1999).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , Perez-StableEJ, HerreraB, JacobP 3rd: Slower metabolism and reduced intake of nicotine from cigarette smoking in Chinese–Americans. J. Natl Cancer Inst.94(2), 108–115 (2002).
   PubMedGoogle Scholar
• Shimada T , YamazakiH, GuengerichFP: Ethnic-related differences in coumarin 7-hydroxylation activities catalyzed by cytochrome P4502A6 in liver microsomes of Japanese and Caucasian populations.Xenobiotica26(4), 395–403 (1996).
   PubMed Web of Science ®Google Scholar
• Fuhr U , JetterA, KirchheinerJ: Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the 'cocktail‘ approach.Clin. Pharmacol. Ther.81(2), 270–283 (2007).
   PubMed Web of Science ®Google Scholar
• Yamazaki H , InoueK, HashimotoM, ShimadaT: Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes.Arch. Toxicol.73(2), 65–70 (1999).
   PubMed Web of Science ®Google Scholar
• Hukkanen J , JacobP 3rd: Benowitz NL: Metabolism and disposition kinetics of nicotine. Pharmacol. Rev.57(1), 79–115 (2005).
   PubMed Web of Science ®Google Scholar
• Dempsey D , TutkaP, JacobP, 3rd et al.: Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin. Pharmacol. Ther.76(1), 64–72 (2004).
   PubMed Web of Science ®Google Scholar
• Yamanaka H , NakajimaM, NishimuraK et al.: Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted. Eur. J. Pharm. Sci.22(5), 419–425 (2004).
   PubMed Web of Science ®Google Scholar
• Malaiyandi V , LermanC, BenowitzNL et al.: Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy. Mol. Psychiatry11(4), 400–409 (2006).
   PubMed Web of Science ®Google Scholar
• Lerman C , TyndaleR, PattersonF et al.: Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation.Clin. Pharmacol. Ther.79(6), 600–608 (2006).
   PubMed Web of Science ®Google Scholar
• Levi M , DempseyDA, BenowitzNL, SheinerLB: Population pharmacokinetics of nicotine and its metabolites I. Model development.J. Pharmacokinet. Pharmacodyn.34(1), 5–21 (2007).
   PubMed Web of Science ®Google Scholar
• Lea RA , DicksonS, BenowitzNL: Within-subject variation of the salivary 3HC/COT ratio in regular daily smokers: prospects for estimating CYP2A6 enzyme activity in large-scale surveys of nicotine metabolic rate.J. Anal. Toxicol.30(6), 386–389 (2006).
   PubMed Web of Science ®Google Scholar
• Levi M , DempseyDA, BenowitzNL, SheinerLB: Prediction methods for nicotine clearance using cotinine and 3-hydroxy-cotinine spot saliva samples II: model application.J. Pharmacokinet. Pharmacodyn.34(1), 23–34 (2007).
   PubMed Web of Science ®Google Scholar
• Mwenifumbo JC , SellersEM, TyndaleRF: Nicotine metabolism and CYP2A6 activity in a population of black African descent: impact of gender and light smoking.Drug Alcohol Depend.89(1), 24–33 (2007).
   PubMed Web of Science ®Google Scholar
• Swan GE , BenowitzNL, LessovCN et al.: Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence.Pharmacogenet. Genomics15(2), 115–125 (2005).
   PubMed Web of Science ®Google Scholar
• Yang M , KunugitaN, KitagawaK et al.: Individual differences in urinary cotinine levels in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes.Cancer Epidemiol. Biomarkers Prev.10(6), 589–593 (2001).
   PubMed Web of Science ®Google Scholar
• Byrd GD , ChangKM, GreeneJM, deBethizyJD: Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans-3´-hydroxycotinine in smokers.Drug Metab. Dispos.20(2), 192–197 (1992).
   PubMed Web of Science ®Google Scholar
• Neurath GB , DungerM, OrthD, PeinFG: Trans-3´-hydroxycotinine as a main metabolite in urine of smokers.Int. Arch. Occup. Environ. Health59(2), 199–201 (1987).
   PubMed Web of Science ®Google Scholar
• Peamkrasatam S , SriwatanakulK, Kiyotani K et al.: In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais. Drug Metab. Pharmacokinet.21(6), 475–484 (2006).
   PubMed Web of Science ®Google Scholar
• Nakajima M , KwonJT, TanakaN et al.: Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans.Clin. Pharmacol. Ther.69(1), 72–78 (2001).
   PubMed Web of Science ®Google Scholar
• Prather RD , TuTG, RolfCN, GorslineJ: Nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) in women and obese men compared with normal-sized men.J. Clin. Pharmacol.33(7), 644–649 (1993).
   PubMed Web of Science ®Google Scholar
• Zeman MV , HirakiL, SellersEM: Gender differences in tobacco smoking: higher relative exposure to smoke than nicotine in women.J. Womens Health Gend. Based Med.11(2), 147–153 (2002).
   PubMedGoogle Scholar
• Benowitz NL , Lessov-SchlaggarCN, Swan GE, Jacob P 3rd: Female sex and oral contraceptive use accelerate nicotine metabolism. Clin. Pharmacol. Ther. (2006) 79(5), 480–488.
   PubMed Web of Science ®Google Scholar
• Dempsey D , JacobP 3rd, Benowitz NL: Accelerated metabolism of nicotine and cotinine in pregnant smokers. J. Pharmacol. Exp. Ther.301(2), 594–598 (2002).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , JacobP 3rd: Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin. Pharmacol. Ther.53(3), 316–323 (1993).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , JacobP 3rd: Effects of cigarette smoking and carbon monoxide on nicotine and cotinine metabolism. Clin. Pharmacol. Ther.67(6), 653–659 (2000).
   PubMed Web of Science ®Google Scholar
• Schoedel KA , SellersEM, PalmourR, TyndaleRF: Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration.Mol. Pharmacol.63(1), 96–104 (2003).
   PubMed Web of Science ®Google Scholar
• Denton TT , ZhangX, CashmanJR: Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6.Biochem. Pharmacol.67(4), 751–756 (2004).
   PubMed Web of Science ®Google Scholar
• von Weymarn LB , BrownKM, MurphySE: Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism.J. Pharmacol. Exp. Ther.316(1), 295–303 (2006).
   PubMed Web of Science ®Google Scholar
• Hakooz N , HamdanI: Effects of dietary broccoli on human in vivo caffeine metabolism: a pilot study on a group of Jordanian volunteers.Curr. Drug Metab.8(1), 9–15 (2007).
   PubMed Web of Science ®Google Scholar
• Anderson GD , RositoG, MohustsyMA, ElmerGW: Drug interaction potential of soy extract and Panax ginseng.J. Clin. Pharmacol.43(6), 643–648 (2003).
   PubMed Web of Science ®Google Scholar
• Schoedel KA , HoffmannEB, RaoY, Sellers EM, Tyndale RF: Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics14(9), 615–626 (2004).
   PubMedGoogle Scholar
• Saeki M , SaitoY, JinnoH et al.: Genetic variations and haplotypes of UGT1A4 in a Japanese population.Drug Metab. Pharmacokinet.20(2), 144–151 (2005).
   PubMedGoogle Scholar
• Bao Z , HeXY, DingX, PrabhuS, HongJY: Metabolism of nicotine and cotinine by human cytochrome P450 2A13.Drug Metab. Dispos.33(2), 258–261 (2005).
   PubMed Web of Science ®Google Scholar
• Koskela S , HakkolaJ, HukkanenJ et al.: Expression of CYP2A genes in human liver and extrahepatic tissues.Biochem. Pharmacol.57(12), 1407–1413 (1999).
   PubMed Web of Science ®Google Scholar
• Su T , BaoZ, ZhangQY et al.: Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.Cancer Res.60(18), 5074–5079 (2000).
   PubMed Web of Science ®Google Scholar
• Gourlay SG , BenowitzNL: Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine.Clin. Pharmacol. Ther.62(4), 453–463 (1997).
   PubMed Web of Science ®Google Scholar
• Miksys S , LermanC, ShieldsPG, MashDC, TyndaleRF: Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain.Neuropharmacology45(1), 122–132 (2003).
   PubMed Web of Science ®Google Scholar
• Gervot L , RochatB, GautierJC et al.: Human CYP2B6: expression, inducibility and catalytic activities.Pharmacogenetics9(3), 295–306 (1999).
   PubMedGoogle Scholar
• Gonzalez FJ , CrespiCL, CzerwinskiM, GelboinHV: Analysis of human cytochrome P450 catalytic activities and expression.Tohoku J. Exp. Med.168(2), 67–72 (1992).
   PubMed Web of Science ®Google Scholar
• Lee AM , JepsonC, ShieldsPG et al.: CYP2B6 genotype does not alter nicotine metabolism, plasma levels, or abstinence with nicotine replacement therapy.Cancer Epidemiol Biomarkers Prev.16(6), 1312–1314 (2007).
   PubMed Web of Science ®Google Scholar
• Russell MA , WilsonC, PatelUA, ColePV, FeyerabendC: Comparison of effect on tobacco consumption and carbon monoxide absorption of changing to high and low nicotine cigarettes.Br. Med. J.4(5891), 512–516 (1973).
   PubMedGoogle Scholar
• Kozlowski LT , JarvikME, GritzER: Nicotine regulation and cigarette smoking.Clin. Pharmacol. Ther.17(1), 93–97 (1975).
   PubMed Web of Science ®Google Scholar
• Benowitz NL , JacobP 3rd: Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J. Pharmacol. Exp. Ther.234(1), 153–155 (1985).
   PubMed Web of Science ®Google Scholar
• Zhang W , KilicarslanT, TyndaleRF, Sellers EM: Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab. Dispos.29(6), 897–902 (2001).
   PubMed Web of Science ®Google Scholar
• Sellers EM , KaplanHL, TyndaleRF: Inhibition of cytochrome P450 2A6 increases nicotine‘s oral bioavailability and decreases smoking.Clin. Pharmacol. Ther.68(1), 35–43 (2000).
   PubMed Web of Science ®Google Scholar
• Sellers EM , TyndaleRF, FernandesLC: Decreasing smoking behaviour and risk through CYP2A6 inhibition.Drug Discov. Today8(11), 487–493 (2003).
   PubMed Web of Science ®Google Scholar
• Gourlay SG , BenowitzNL, ForbesA, McNeilJJ: Determinants of plasma concentrations of nicotine and cotinine during cigarette smoking and transdermal nicotine treatment.Eur. J. Clin. Pharmacol.51(5), 407–414 (1997).
   PubMed Web of Science ®Google Scholar
• Sachs DP : Effectiveness of the 4-mg dose of nicotine polacrilex for the initial treatment of high-dependent smokers.Arch. Intern. Med.155(18), 1973–1980 (1995).
   PubMedGoogle Scholar
• Malaiyandi V , SellersEM, TyndaleRF: Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence.Clin. Pharmacol. Ther.77(3), 145–158 (2005).
   PubMed Web of Science ®Google Scholar
• Audrain-McGovern J , Al Koudsi N, Rodriguez D et al.: The role of CYP2A6 in the emergence of nicotine dependence in adolescents. Pediatrics119(1), E264–E274 (2007).
   PubMed Web of Science ®Google Scholar
• O‘Loughlin J , ParadisG, KimW et al.: Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers.Tob. Control13(4), 422–428 (2004).
   PubMed Web of Science ®Google Scholar
• Iwahashi K , WagaC, TakimotoT: Whole deletion of CYP2A6 gene (CYP2A6AST;4C) and smoking behavior.Neuropsychobiology49(2), 101–104 (2004).
   PubMed Web of Science ®Google Scholar
• Minematsu N , NakamuraH, FuruuchiM et al.: Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms. Eur. Respir. J.27(2), 289–292 (2006).
   PubMed Web of Science ®Google Scholar
• Ariyoshi N , KitadaM, KamatakiT: Association between genetic polymorphism and lung cancer risk.Nippon Rinsho60(Suppl. 5), 46–49 (2002).
   PubMedGoogle Scholar
• Fujieda M , YamazakiH, SaitoT et al.: Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers.Carcinogenesis25(12), 2451–2458 (2004).
   PubMed Web of Science ®Google Scholar
• Strasser AA , MalaiyandiV, HoffmannE, TyndaleRF, LermanC: An association of CYP2A6 genotype and smoking topography.Nicotine Tob. Res.9(4), 511–518 (2007).
   PubMed Web of Science ®Google Scholar
• Malaiyandi V , GoodzSD, SellersEM, TyndaleRF: CYP2A6 genotype, phenotype, and the use of nicotine metabolites as biomarkers during ad libitum smoking.Cancer Epidemiol. Biomarkers Prev.15(10), 1812–1819 (2006).
   PubMed Web of Science ®Google Scholar
• Gu DF , HinksLJ, MortonNE, DayIN: The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit.Ann. Hum. Genet.64(Pt 5), 383–390 (2000).
   PubMed Web of Science ®Google Scholar
• Carter B , LongT, CinciripiniP: A meta-analytic review of the CYP2A6genotype and smoking behavior.Nicotine Tob. Res.6(2), 221–227 (2004).
   PubMed Web of Science ®Google Scholar
• Munafo M , ClarkT, JohnstoneE, Murphy M, Walton R: The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob. Res.6(4), 583–597 (2004).
   PubMed Web of Science ®Google Scholar
• Hecht SS : Approaches to cancer prevention based on an understanding of N-nitrosamine carcinogenesis.Proc. Soc. Exp. Biol. Med.216(2), 181–191 (1997).
   PubMed Web of Science ®Google Scholar
• Hecht SS : DNA adduct formation from tobacco-specific N-nitrosamines.Mutat. Res.424(1–2), 127–142 (1999).
   PubMed Web of Science ®Google Scholar
• Hecht SS : Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines.Chem. Res. Toxicol.11(6), 559–603 (1998).
   PubMed Web of Science ®Google Scholar
• Perera FP : Environment and cancer: who are susceptible?Science278(5340), 1068–1073 (1997).
   PubMed Web of Science ®Google Scholar
• Wang H , TanW, HaoB et al.: Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK.Cancer Res.63(22), 8057–8061 (2003).
   PubMed Web of Science ®Google Scholar
• Tan W , ChenGF, XingDY et al.: Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population.Int J. Cancer95(2), 96–101 (2001).
   PubMed Web of Science ®Google Scholar
• Kamataki T , NunoyaK, SakaiY, KushidaH, FujitaK: Genetic polymorphism of CYP2A6 in relation to cancer.Mutat. Res.428(1–2), 125–130 (1999).
   PubMed Web of Science ®Google Scholar
• Miyamoto M , UmetsuY, Dosaka-AkitaH et al.: CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem. Biophys. Res. Commun.261(3), 658–660 (1999).
   PubMed Web of Science ®Google Scholar
• London SJ , IdleJR, DalyAK, CoetzeeGA: Genetic variation of CYP2A6, smoking and risk of cancer.Lancet353(9156), 898–899 (1999).
   PubMed Web of Science ®Google Scholar
• Loriot MA , RebuissouS, OscarsonM et al.: Genetic polymorphisms of cytochrome P450 2A6 in a case–control study on lung cancer in a French population.Pharmacogenetics11(1), 39–44 (2001).
   PubMedGoogle Scholar
• Ariyoshi N , TakahashiY, MiyamotoM et al.: Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C. Pharmacogenetics10(8), 687–693 (2000).
   PubMedGoogle Scholar
• Nakajima M , YoshidaR, FukamiT, McLeod HL, Yokoi T: Novel human CYP2A6 alleles confound gene deletion analysis. FEBS Lett.569(1–3), 75–81 (2004).
   PubMed Web of Science ®Google Scholar
• Oscarson M , McLellanRA, GullstenH et al.: Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett.448(1), 105–110 (1999).
   PubMed Web of Science ®Google Scholar
• Nunoya K , YokoiT, KimuraK et al.: A new deleted allele in the human cytochrome P450 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).Pharmacogenetics8(3), 239–249 (1998).
   PubMedGoogle Scholar
• Nunoya K , YokoiT, TakahashiY et al.: Homologous unequal cross-over within the human CYP2A gene cluster as a mechanism for the deletion of the entire CYP2A6 gene associated with the poor metabolizer phenotype.J. Biochem. (Tokyo)126(2), 402–407 (1999).
   PubMed Web of Science ®Google Scholar
• Nunoya KI , YokoiT, KimuraK 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.289(1), 437–442 (1999).
   PubMed Web of Science ®Google Scholar
• Ariyoshi N , SekineH, SaitoK, KamatakiT: Characterization of a genotype previously designated as CYP2A6 D-type: CYP2A6*4B, another entire gene deletion allele of the CYP2A6 gene in Japanese.Pharmacogenetics12(6), 501–504 (2002).
   PubMedGoogle Scholar
• Ariyoshi N , SawamuraY, KamatakiT: A novel single nucleotide polymorphism altering stability and activity of CYP2A6.Biochem. Biophys. Res. Commun.281(3), 810–814 (2001).
   PubMed Web of Science ®Google Scholar
• Yoshida R , NakajimaM, WatanabeY, Kwon JT, Yokoi T: Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br. J. Clin. Pharmacol.54(5), 511–517 (2002).
   PubMed Web of Science ®Google Scholar
• Yoshida R , NakajimaM, NishimuraK et al.: 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.74(1), 69–76 (2003).
   PubMed Web of Science ®Google Scholar
• Nurfadhlina M , FoongK, TehLK et al.: CYP2A6 polymorphisms in Malays, Chinese and Indians.Xenobiotica36(8), 684–692 (2006).
   PubMed Web of Science ®Google Scholar
• Gambier N , BattAM, MarieB et al.: Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort.Pharmacogenomics J.5(4), 271–275 (2005).
   PubMed Web of Science ®Google Scholar
• Huang S , CookDG, HinksLJ et al.: CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents.Pharmacogenet. Genomics15(12), 839–850 (2005).
   PubMed Web of Science ®Google Scholar
• Gyamfi MA , FujiedaM, KiyotaniK, YamazakiH, KamatakiT: High prevalence of cytochrome P450 2A6*1A alleles in a black African population of Ghana.Eur. J. Clin. Pharmacol.60(12), 855–857 (2005).
   PubMed Web of Science ®Google Scholar

Website

• CYP2A6 allele nomenclature (2001) www.cypalleles.ki.se/cyp2a6.htm
   Google Scholar