Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians.

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).

[1]  M. Jarvik,et al.  Nicotine Blood Levels and Subjective Craving for Cigarettes , 2000, Pharmacology Biochemistry and Behavior.

[2]  K. Matsuo,et al.  Association of CYP2A6 Gene Deletion with Cigarette Smoking Status in Japanese Adults , 2003, Journal of epidemiology.

[3]  M. Ingelman-Sundberg,et al.  Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. , 2001, Biochemical and biophysical research communications.

[4]  Jennifer A. Ferguson,et al.  Predictors of 6-month tobacco abstinence among 1224 cigarette smokers treated for nicotine dependence. , 2003, Addictive behaviors.

[5]  R. Tyndale,et al.  Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers , 2004, Tobacco Control.

[6]  R. Tyndale,et al.  The effect of methoxsalen on nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in vivo. , 2003, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[7]  S. Lai,et al.  The Association Between Cigarette Smoking and Drug Abuse in the United States , 2000, Journal of addictive diseases.

[8]  B. Green,et al.  Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method. , 1999, Pharmacogenetics.

[9]  J. Mackenbach,et al.  Why do lower educated people continue smoking? Explanations from the longitudinal GLOBE study. , 2002, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[10]  R. Foxx,et al.  Nicotine's role in smoking: an analysis of nicotine regulation. , 1983, Psychological bulletin.

[11]  R. Tyndale,et al.  Genotyping human CYP2A6 variants. , 2002, Methods in enzymology.

[12]  R. Kessler,et al.  Nicotine dependence in the United States: prevalence, trends, and smoking persistence. , 2001, Archives of general psychiatry.

[13]  Jun Yokota,et al.  Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[14]  M. Loriot,et al.  Genetic polymorphisms of cytochrome P450 2A6 in a case-control study on lung cancer in a French population. , 2001, Pharmacogenetics.

[15]  N. Martin,et al.  The Genetics of Smoking Persistence in Men and Women: A Multicultural Study , 1999, Behavior genetics.

[16]  D. Hamer,et al.  An Improved Assay Shows No Association Between the CYP2A6 Gene and Cigarette Smoking Behavior , 1999 .

[17]  S. Tokudome,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 , 2003, Clinical pharmacology and therapeutics.

[18]  M. Djordjevic,et al.  Nicotine regulates smoking patterns. , 1997, Preventive medicine.

[19]  J. S. Miles,et al.  Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity. , 1990, The Biochemical journal.

[20]  M. Ingelman-Sundberg,et al.  Characterisation and PCR‐based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population , 1999, FEBS letters.

[21]  R. Tyndale,et al.  An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. , 2002, Biochemical and biophysical research communications.

[22]  P. Batel,et al.  Relationship between alcohol and tobacco dependencies among alcoholics who smoke. , 1995, Addiction.

[23]  M. Tsuang,et al.  Genetic and environmental contributions to smoking. , 1997, Addiction.

[24]  M. Mayo,et al.  Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial. , 2002, JAMA.

[25]  N E Morton,et al.  The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit , 2000, Annals of human genetics.

[26]  K Chiba,et al.  Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  R. Tyndale,et al.  Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. , 2000, Molecular pharmacology.

[28]  C. Gevirtz,et al.  Outcome and Six Month Follow Up of Patients After Ultra Rapid Opiate Detoxification (URODSM) , 2000, Journal of addictive diseases.

[29]  K. Kendler,et al.  Tobacco consumption in Swedish twins reared apart and reared together. , 2000, Archives of general psychiatry.

[30]  R. Tyndale,et al.  Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking , 2000, Clinical pharmacology and therapeutics.

[31]  R. Tyndale,et al.  Genetics of alcohol and tobacco use in humans , 2003, Annals of medicine.

[32]  O Pelkonen,et al.  Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism , 1999, FEBS letters.

[33]  S. Anttila,et al.  Expression of CYP2A genes in human liver and extrahepatic tissues. , 1999, Biochemical pharmacology.

[34]  M. Kitagawa,et al.  CYP2A6*6, a Novel Polymorphism in Cytochrome P450 2A6, Has a Single Amino Acid Substitution (R128Q) That Inactivates Enzymatic Activity* , 2001, The Journal of Biological Chemistry.

[35]  K. Iwahashi,et al.  Whole Deletion of CYP2A6 Gene (CYP2A6*4C) and Smoking Behavior , 2004, Neuropsychobiology.

[36]  Y. Funae,et al.  Role of human cytochrome P4502A6 in C-oxidation of nicotine. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[37]  P. Gahlinger,et al.  Computer Programs for Epidemiologists: Pepi Version 4.0 , 2001 .

[38]  M. Nakajima,et al.  Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. , 2002, British journal of clinical pharmacology.

[39]  S. Fujishima,et al.  Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema , 2003, Thorax.

[40]  R. Tyndale,et al.  Assessment of nicotine dependence symptoms in adolescents: a comparison of five indicators. , 2002, Tobacco control.

[41]  L. Kozlowski,et al.  The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. , 1991, British journal of addiction.

[42]  R. Tyndale,et al.  Mimicking Gene Defects to Treat Drug Dependence , 2000, Annals of the New York Academy of Sciences.

[43]  R. Tyndale,et al.  A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. , 1997, The Journal of pharmacology and experimental therapeutics.

[44]  M. Ingelman-Sundberg,et al.  Characterization of a novel CYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity , 2002, Human mutation.

[45]  J. Kugler,et al.  Disabilities, quality of life, and mental disorders associated with smoking and nicotine dependence. , 2003, The American journal of psychiatry.

[46]  N. Benowitz,et al.  Nicotine dependence and tolerance in man: pharmacokinetic and pharmacodynamic investigations. , 1989, Progress in brain research.

[47]  Hiroshi Yamamoto,et al.  Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans , 2001, Clinical pharmacology and therapeutics.

[48]  N. Benowitz,et al.  Metabolism of nicotine to cotinine studied by a dual stable isotope method , 1994, Clinical pharmacology and therapeutics.

[49]  H. Yamazaki,et al.  CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation activities in Japanese and Caucasians , 2000, Archives of Toxicology.

[50]  P. Fernández-Salguero,et al.  The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis. , 1995, Pharmacogenetics.

[51]  G. Bepler,et al.  Comparison of cytochrome P450 2A6 polymorphism frequencies in Caucasians and African-Americans using a new one-step PCR-RFLP genotyping method. , 2001, Toxicology.

[52]  T. Kamataki,et al.  Predicting the mutagenicity of tobacco‐related N‐nitrosamines in humans using 11 strains of Salmonella typhimurium YG7108, each coexpressing a form of human cytochrome P450 along with NADPH–cytochrome P450 reductase , 2001, Environmental and molecular mutagenesis.