CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation

Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita City, Japan.
The Pharmacogenomics Journal (Impact Factor: 4.23). 01/2006; 6(2):115-9. DOI: 10.1038/sj.tpj.6500348
Source: PubMed


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.

Download full-text


Available from: Yasushi Fujio, Apr 01, 2014
  • Source
    • "Genetic polymorphism is reported for CYP2A6 in humans and individuals with variant genotypes of CYP2A6 are at a lesser risk to smoking induced lung cancer or head and neck cancer (Camus et al., 1993; Nakajima et al., 2004; Rossini et al., 2008; Matsuda et al., 2007; Oscarson, 2001; Ruwali et al., 2009). It has been reported that poor metabolizers of CYP2A6 have the tendency to smoke less when compared to those with normal metabolizer genotype (Kubota et al., 2006; Malaiyandi et al., 2005; Tyndale and Sellers, 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: 1. The present study aimed to identify the expression of carcinogen metabolizing cytochrome P4502A (CYP2A) isoenzymes in freshly prepared rat peripheral blood lymphocytes (PBL) isolated from adult rats and investigate similarities in the regulation of lymphocyte CYP2A-isoenzymes with the tissue enzyme. 2. qRT-PCR studies demonstrated significant constitutive mRNA expression of CYP2A-isoenzymes in PBL isolated from male and female rats which further increases significantly after pretreatment with nicotine or 3-methylcholanthrene (MC) indicating responsiveness of CYP2A-isoenzymes in PBL. This increase in the CYP2A expression was associated with an increase in the protein expression and CYP2A3-dependent coumarin hydroxylase (COH) activity in PBL. 3. Clinical studies further demonstrated significant increase in the expression of CYP2A6 and associated enzyme activity in PBL isolated from lung cancer patients. Our data thus provided evidence for similarities in the regulation of carcinogen metabolizing CYP2A-isoenzymes in PBL with the tissue enzymes. Further, responsiveness of blood CYP2A6 in human blood lymphocytes isolated from lung cancer patients has led us to suggest that associating expression profiles of CYP2A6 and other polycyclic aromatic hydrocarbons (PAH)-responsive CYPs in PBL with the genotyping data could lead to the development of a possible screen to monitor and predict environment-induced diseases and toxicity in humans.
    Full-text · Article · Aug 2012 · Xenobiotica
  • Source
    • " nicotine may alter sensitivity to these behavioral effects of nicotine . For example , the gene encoding cytochrome P450 2A6 ( CYP2A6 ) , an enzyme that metabolizes nicotine into coti - nine ( Benowitz and Jacob 1994 ; Hukkanen et al . 2005 ) , has been associated with smoking phenotypes in humans ( Pianezza et al . 1998 ; Schoedel et al . 2004 ; Kubota et al . 2006 ) and a study investigating the ortholog of CYP2A6 in mice ( Cyp2a5 ) has shown that low levels of nicotine self - administration in male mice are associated with reduced nicotine metabolism and low CYP2A5 protein levels ( Siu et al . 2006 ) . In the present study , plasma nicotine and cotinine samples were collected from mice treated w"
    [Show abstract] [Hide abstract]
    ABSTRACT: The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction.
    Full-text · Article · Aug 2011 · Behavior Genetics
  • Source
    • ") and in the rate at which they progress to increasingly severe dependence (Audrain-McGovern et al., 2007). Among adult smokers, slow metabolizers are less prevalent than intermediate or normal metabolizers; they smoke fewer cigarettes per day, exhibit reduced cigarette puffing, have decreased dependence, wait longer to smoke the first cigarette of the day, and have fewer nicotine withdrawal symptoms; and they make up a smaller portion of smokers as the duration of smoking increases, suggesting that they quit smoking sooner (Kubota et al., 2006; Malaiyandi et al., 2006; Schoedel et al., 2004; Strasser et al., 2007). These findings suggest that nicotine levels remain elevated longer in smokers with slow-metabolizing CYP2A6 variants than those with fast-metabolizing variants, resulting in a decreased need to light up or puff as often to avoid withdrawal. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacogenetics research looks at variations in the human genome and ways in which genetic factors might influence how individuals respond to drugs. The authors review basic principles of pharmacogenetics and cite findings from several gene-phenotype studies to illustrate possible associations between genetic variants, drug-related behaviors, and risk for drug dependence. Some gene variants affect responses to one drug; others, to various drugs. Pharmacogenetics can inform medication development and personalized treatment strategies; challenges lie along the pathway to its general use in clinical practice.
    Full-text · Article · Dec 2010 · Addiction science & clinical practice
Show more