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Approximately one-third of the global population over 15 years of age smokes, despite the association of this activity with a higher incidence of many diseases including cancers and respiratory and cardiovascular disorders. In humans, 60-80% of nicotine that results from smoking is metabolized to cotinine2, principally by the genetically polymorphic CYP2A6 enzyme3,4. Three CYP2A6 alleles have been identified: the wild-type (CYP2A6*1) and two null, or inactive, alleles (CYP2A6*2 and CYP2A6*3)5.

We considered that there would be an under-representation of individuals with impaired nicotine metabolism (carriers of null CYP2A6 alleles) in a tobacco-dependent population. Genotype frequencies for CYP2A6 alleles5 were quantified in three groups: a tobacco-dependent group (TD, n=164, 52% male) defined by DSM-IV and Fagerstrom criteria, an alcohol- and tobacco-dependent group (AT, n=80, 84% male), and a never-tobacco-dependent exposure control group who had each tried smoking but had never become dependent (NTD, n=184, 52% male). Subjects in all groups had no other psychoactive drug dependencies (DSM-IV criteria). We found that, among all dependent smokers (TD + AT), the frequency of individuals with impaired nicotine metabolism (carriers of 1 or 2 CYP2A6-null alleles) was lower than in the control group (12.3% versus 19.6%, P<0.04, chi-square; odds ratio=1.74, 95% confidence intervals 1.02-2.94; Fig. 1a). These data show that impaired nicotine metabolism protects a smoker against becoming dependent: in fact, even a single CYP2A6-null allele (that is, heterozygosity) is sufficient to significantly reduce the risk of tobacco-dependence.

Figure 1: Effect of CYP2A6-null alleles on tobacco dependence.
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a, Percentage of individuals carrying CYP2A6-null alleles (1 or 2) in the never-tobacco-dependent exposure control group (NTD), and the combined tobacco-dependent (TD) and alcohol- and tobacco-dependent (AT) groups. b, Number of cigarettes smoked per week (mean = s.e.m.) within the TD group is lower for individuals carrying a CYP2A6-null allele. No significant difference in age between groups (P=0.05); WT/WT: CYP2A6*1/*1; WT/mut: CYP2A6*1/*2 + CYP2A6*1/*3.

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Dependent smokers adjust their smoking to maintain constant blood and brain nicotine concentrations6,7. Therefore we tested whether dependent smokers with impaired nicotine metabolism would need to smoke fewer cigarettes. Within the TD group, those heterozygous for CYP2A6-null alleles smoked significantly fewer cigarettes per week than smokers with two CYP2A6active alleles (129 versus 159 cigarettes per week; t-test P<0.02; Fig. 1b). These data suggest that CYP2A6-mediated nicotine metabolism is a significant determinant of the number of cigarettes consumed by dependent smokers and that heterozygosity in a single gene, the CYP2A6 gene, significantly decreases this complex drug-taking behaviour.

Individuals carrying CYP2A6-null alleles may have a decreased risk of developing tobacco-related cancers8 and other medical complications because they have a decreased risk of becoming a smoker and, if they do become dependent, they smoke less than those without impaired nicotine metabolism. As tobacco smoke contains nitrosamines which can be activated to carcinogens by CYP2A6 (refs 910), individuals who carry CYP2A6-null alleles may also be less efficient at activating tobacco-smoke procarcinogens to carcinogens. These three factors may explain why there could be a reduction in tobacco related cancers for carriers of CYP2A6-null alleles.

CYP2A6 genotype may significantly affect nicotine levels from nicotine sources other than cigarettes, such as nicotine-replacement therapies (for example, patch, gum, spray). This may be of growing importance as such therapies are used increasingly for long-term maintenance against tobacco dependence and for treatment of other syndromes (such as Alzheimer's disease, Tourette's syndrome, ulcerative colitis). In addition, the protective effect of CYP2A6-null alleles against the risk of becoming tobacco-dependent and in decreasing consumption suggests that inhibiting this enzyme may be a new way to help prevent and treat tobacco smoking.