CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation.
ABSTRACT 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.
- SourceAvailable from: onlinelibrary.wiley.com[Show abstract] [Hide abstract]
ABSTRACT: Evidence suggests that both the nicotinic receptor α5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes. Placebo-controlled randomized smoking cessation trial SETTING: Ambulatory care facility in Wisconsin, USA. Smokers (N=709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy, or combined bupropion and nicotine replacement therapy. Survival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function. CYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days (Hazard Ratio (HR) = 2.81, 95%CI=1.32-5.99, p=0.0075), with pharmacotherapy significantly slowing relapse in fast (HR=0.39, 95%CI=0.28-0.55, p=1.97x10-8), but not slow, metabolizers (HR=1.09, 95%CI=0.55-2.17, p=0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (interaction effect size=0.74, 95%CI=0.59-0.94, p=0.013). Nicotine replacement therapy is effective amongst individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses amongst smokers with genes may guide future personalized smoking cessation interventions.Addiction 09/2013; · 4.60 Impact Factor
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ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a complex genetic disease that develops as a result of the interaction of multiple susceptibility genes and environmental factors. Major therapeutic approaches include smoking cessation, treatment with bronchodilators and corticosteroid therapy. The goal of understanding the genetic defects in patients with COPD will be not only to redefine the disease phenotypes based on the genetic information, but also to alternatively approach patients based on the understanding of COPD pathogenesis, which will lead to improved clinical outcomes. Although there is no single ideal phenotype for COPD pharmacogenetic studies, thus far, most pharmacogenetics studies have focused on the role of variants in the β2-adrenergic receptor gene on bronchodilator response. The inconclusive results yielded by these studies highlight many of the difficulties researchers face in assessing the influence of genetic variants and in translating this to clinically relevant outcomes.Pharmacogenomics 07/2013; 14(10):1215-25. · 3.43 Impact Factor
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ABSTRACT: Background This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects¿ smoking history on the association.ResultsGenotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence.Conclusions This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.BMC Genetics 12/2014; 15(1):151. · 2.36 Impact Factor
CYP2A6 polymorphisms are associated with
nicotine dependence and influence withdrawal
symptoms in smoking cessation
T Kubota1,4, C Nakajima-
Taniguchi2,4, T Fukuda1,
M Funamoto3, M Maeda1,
E Tange1, R Ueki1, K Kawashima1,
H Hara2, Y Fujio1and J Azuma1
1Department of Clinical Evaluation of Medicines
and Therapeutics, Graduate School of
Pharmaceutical Sciences, Osaka University,
Yamadaoka, Suita City, Osaka, Japan;2Osaka
Regional Taxation Bureau’s Clinic, Otemae,
Chuo-ku, Osaka 540-0008, Japan and
3Funamoto Clinic, Urakaze-cho, Koshien,
Hyogo 663-8165, Japan
Professor J Azuma, Department of Clinical
Evaluation of Medicines and Therapeutics,
Graduate School of Pharmaceutical Sciences,
Osaka University, 1-6 Yamadaoka, Suita City,
Osaka 565-0871, Japan.
4These authors contributed equally to this
September 2005; accepted 20 September
2005; published online 10 January 2006
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 (n¼107)
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.
The Pharmacogenomics Journal (2006) 6, 115–119. doi:10.1038/sj.tpj.6500348;
published online 10 January 2006
Keywords: CYP2A6; polymorphism; smoking; nicotine; individualized medicine
Smoking is one of the most important risk factors for serious diseases, including
cancers, chronic obstructive pulmonary diseases and cardiovascular diseases. It is
strongly recommended that smokers should cease smoking for good health.
However, there is an interindividual diversity in the difficulties in quitting
smoking, mainly due to nicotine dependence. Therefore, to carry out smoking
cessation program effectively, individual status of smoking should be estimated
and, more importantly, predicted, based on nicotine dependence.
Nicotine is metabolized to cotinine, an inactive metabolite, principally by
CYP2A6.1Several CYP2A6 gene polymorphisms have been identified so far, and
three alleles, *1, *4 and *9, are shown to be the major polymorphisms in
Japanese. CYP2A6*1 is a wild-type allele with normal enzyme activity. CYP2A6*4
is a whole deletion type of the CYP2A6 gene.2,3CYP2A6*9 has a single-nucleotide
polymorphism in TATA box, T-48G substitution, which impairs the transcrip-
tional activities4and, consequently, its enzymatic activity.5,6It has been clearly
demonstrated that the pharmacokinetics of nicotine is influenced by CYP2A6
The Pharmacogenomics Journal (2006) 6, 115–119
& 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00
In the present study, as pharmacokinetic changes in
plasma nicotine concentration are considered to be related
with craving for nicotine,7we hypothesized that CYP2A6
polymorphisms might affect smoking status. And we
evaluated the relation between CYP2A6 genotypes and
smoking habits, including nicotine withdrawal symptoms,
from the point of view of nicotine dependence. The data
presented here provide insights into individualized smoking
cessation program based on CYP2A6 genotypes.
First, we confirmed the relationship between the CYP2A6
genotypes and the number of cigarettes in the subjects
analyzed in the present study (Figure 1a). In vivo enzymatic
CYP2A6*1/*1, *1/*9, *1/*4, *9/*9, *4/*9 and *4/*4.5CYP2A6
genotype, which determines the enzyme activity in vivo, had
a tendency to be associated with the number of cigarettes
smoked per day, as reported previously.8–10Next, the
amounts of daily nicotine intake were also examined. As
shown in Figure 1b, CYP2A6 genotype is likely to be linked
with daily nicotine intake, proposing the possible associa-
tion between CYP2A6 genotypes and nicotine dependence.
Association between CYP2A6 genotypes and smoking
habits, such as the number of the cigarettes per day and
The subjects were divided into the high- and low-activity
group, based on their CYP2A6 genotypes, according to the
previous study.5The subjects with the *1/*1, *1/*9, *1/*4 and
*9/*9 genotypes, whose metabolic activities of nicotine
are more than 70% of those of the subjects with *1/*1, were
defined as high-activity group, whereas the subjects with the
*4/*9 and *4/*4 genotypes with less than 50% of metabolic
activities of the subjects with *1/*1 as low-activity group.
It was found that the associations of CYP2A6 genotypes
with the number of cigarettes or with the nicotine
uptake approached statistical significance (P¼0.09 or 0.06,
To evaluate nicotine dependence more directly, we
analyzed the relation between CYP2A6 genotypes and the
time to the first cigarette as described in Materials and
methods. As shown in Figure 2, proportion of subjects who
smoked the first cigarette within 5min of waking up was
significantly higher in CYP2A6 high-activity group than in
low-activity group (36.8%, n¼95 and 8.3%, n¼12, respec-
tively, Po0.05), suggesting that the subjects with high
CYP2A6 activity show the severer nicotine dependence than
those with low activity.
Fagerstrom Test for Nicotine Dependence (FTND) is
commonly performed to estimate nicotine dependence.
Thus, the relationship between CYP2A6 genotypes and
nicotine dependence was evaluated according to FTND.
Consistent with the results shown in Figure 2, there was
significant association between the total score of FTND and
3.1770.94 in low-activity group, Po0.05) (Figure 3).
Finally, nicotine dependence was diagnosed according
to the severity of withdrawal symptoms observed during
smoking cessation. In the population of smokers who tried
to quit smoking, withdrawal syndrome was categorized into
of cigarettes smoked per day (a) or the amount of daily nicotine intake
(b). CYP2A6 genotypes had a tendency to be associated with the
number of cigarettes smoked per day (n¼107, P¼0.09) and the
amount of daily nicotine intake (n¼70, P¼0.06).
Relationship between the CYP2A6 genotypes and the number
of the day. The proportion of subjects who smoked the first cigarette
within 5min of waking up was calculated, as an index for nicotine
dependence. The proportion of subjects was significantly higher in
CYP2A6 high-activity group than in low-activity group. CYP2A6 high-
activity group consists of subjects carrying CYP2A6*1/*1, *1/*9, *1/*4
and *9/*9. Low-activity group consists of subjects carrying CYP2A6*4/*9
CYP2A6 genotypes were related to time to the first cigarette
CYP2A6 polymorphisms in smoking cessation
T Kubota et al
The Pharmacogenomics Journal
three groups: severe, moderate and weak. The proportion of
subjects with severe withdrawal symptoms was higher in
CYP2A6 high-activity group than in low-activity group
(Figure 4a). The proportion of subjects was 50.0, 44.4 and
5.6% for severe, moderate and weak withdrawal symptoms,
respectively, in high-activity group (n¼72), and 22.2, 44.4
and 33.3%, respectively, in low-activity group (n¼9) (w2test;
Po0.05). Furthermore, as nicotine replacement therapy
affects the withdrawal symptoms, the degree of withdrawal
symptoms was compared in the subpopulation that tried to
quit smoking by receiving nicotine replacement therapy.
The proportion of subjects was 60.4, 37.5 and 2.1% for
severe, moderate and weak symptom, respectively, in high-
activity group (n¼48), and 33.3, 16.7 and 50.0%, respec-
tively, in low-activity group (n¼6) (w2test; Po0.01; Figure
4b). To clarify the association between the CYP2A6 activities
and nicotine dependence, the odds ratios (ORs) with 95%
confidence intervals (CIs) were estimated relatively to the
subjects with the weak withdrawal symptoms. In the total
subjects, the ORs (95% CIs) were 6.0 (0.97–37.12, P¼0.128)
for the moderate and 13.5 (1.71–106.56, P¼0.025) for the
severe, respectively. In the subpopulation, they are 54.0
(2.61–1116.96, P¼0.0089) for the moderate and 43.5 (2.99–
633.62, P¼0.00341) for the severe, respectively. Collec-
tively, the relation between severities of withdrawal symp-
toms and CYP2A6 genotypes is more clearly demonstrated
in this subpopulation.
In the present study, we have demonstrated that CYP2A6
mutant allele with impaired or null enzyme activity was a
negative risk factor for habit of smoking, especially nicotine
First, the number of cigarettes per day was likely to be
associated with the activity of CYP2A6. Relation between
the number of cigarettes and CYP2A6 genotype has been
analyzed in several studies, with inconsistent results. Some
studies have also shown that subjects who possessed
CYP2A6 mutant allele smoked fewer cigarettes,8–10as is the
case with the present study, whereas others reported that
CYP2A6 genotypes are not associated with cigarettes con-
sumption in Japanese,11–13Chinese14and Caucasians.15As
smoking behavior is also influenced by environmental
factors, these conflicting results might be due to interindi-
vidual differences in the environmental factors including
lifestyles. In this study, a majority of the subjects were
working as ‘white collar workers’, so difference in environ-
mental influence was expected to be minimized.
To our knowledge, this is the first report that evaluated
the relationship between the time to the first cigarette of the
day and CYP2A6 genotypes. And it is revealed that the
subjects with high-activity alleles of CYP2A6 smoke the first
cigarette earlier than those with low activity. Importantly, as
the time to the first cigarette of the day is considered to be
influenced by nicotine dependence, it is possible that
CYP2A6 activity is related with nicotine dependence. To
address this possibility, nicotine dependence was quantified
by calculating the score on the number of cigarettes per day
and the time to the first cigarette of the day, according to
FTND score. These two items are most important factors of
FTND score,16and are generally used in smoking cessation
program. As a result, nicotine dependence was more
remarkable in the subjects with CYP2A6 high activity than
in those with low activity.
Finally, we investigated the relationship between nicotine
withdrawal symptoms and CYP2A6 genotypes. It was
revealed that the subjects in CYP2A6 high-activity group
the subpopulation that tried to quit smoking. Degree of withdrawal
symptoms was evaluated using a questionnaire. (a) In CYP2A6 high-
activity group, the withdrawal symptoms were significantly more serious
than the low-activity group. (b) Degree of withdrawal symptoms and
CYP2A6 genotypes in the population that tried to quit smoking by
receiving nicotine replacement therapy. Among the population that
tried to quit smoking by receiving nicotine replacement therapy, severe
withdrawal symptoms were more remarkable in CYP2A6 high-activity
group than in low activity group.
Impacts of CYP2A6 genotypes on withdrawal symptoms in
analyzed by Fagerstrom Test for Nicotine Dependence. A total score for
nicotine dependence was calculated by total scores on self-reported
number of cigarettes smoked per day and time to the first cigarette of
the day. The score was significantly high in CYP2A6 high-activity group,
compared to low-activity group. Data are shown as mean7s.d.
CYP2A6 genotypes are associated with nicotine dependence,
CYP2A6 polymorphisms in smoking cessation
T Kubota et al
The Pharmacogenomics Journal
exhibited manifest withdrawal symptoms, which are clinical
phenotypes derived from nicotine dependence in smoking
cessation. Moreover, the correlation between CYP2A6
genotypes and withdrawal symptoms is more remarkable
in subjects who received nicotine replacement therapy.
Recent studies have provided molecular and cellular aspects
of nicotine abuse. From the neuroscientific point of view,
withdrawal symptom is considered to be the process of the
nicotinic acetylcholine receptor from desensitization/inac-
tivation states to functional states.17Importantly, low
concentrations of nicotine cause desensitization of its
receptors. Therefore, the smokers with high CYP2A6 activity
might maintain a low level of nicotine that may inactivate a
larger number of nicotinic receptors, compared with those
with low activity. As a result, after many hours of
abstinence, an excessive number of desensitized/inactivated
nicotine receptors may begin to recover to functional states
in the smokers with high CYP2A6 activity, resulting in the
severe withdrawal symptoms.
In the process of smoking cessation, a number of smokers
receive nicotine replacement therapy. High dose of nicotine
is administered, for example, with nicotine patch, at the
starting point and the subjects gradually weaned themselves
from nicotine by reducing the dosage according to the
generalized cessation protocol. Considering that the sub-
jects with high CYP2A6 activity are prone to nicotine
dependence, it might be beneficial to individualize the
protocol for nicotine replacement therapy. Theoretically, by
reducing the dosage of nicotine more deliberately in the
subjects with high activity than in those with low activity,
the success rate in quitting smoking would be improved. At
the same time, we have also noticed the limitation of the
individualized program for smoking cessation based on
CYP2A6 genotypes alone. It is likely that other gene
polymorphisms, in addition to CYP2A6, might be involved
in nicotine dependence, because interindividual differences
were not completely canceled by classifying the subjects
based on CYP2A6 genotypes. Further investigation may be
required to understand the genetic background of the
susceptibility to nicotine dependence.
In conclusion, we found that CYP2A6 genotypes affect
smoking habit, nicotine dependence, and withdrawal
symptoms during smoking cessation. It could be proposed
that CYP2A6 genotyping may be a novel pharmacogenomic
strategy for smoking cessation program as an individualized
Materials and methods
This study is designed as a multicenter trial. The study
subjects consisted of 107 Japanese smokers who attended to
a clinic for their health care. The patients with life-
threatening diseases, including cancer, heart failure and
symptomatic chronic obstructive pulmonary diseases, were
excluded. All subjects gave their informed consent to
participate in this study.
This study was approved by the institutional review
committee of Osaka University.
Estimation of smoking status
All subjects were interviewed about their smoking habits
such as the number of cigarettes per day, the nicotine
content of the cigarettes, which they usually smoke, and
time to the first cigarette of the day, which is generally
accepted as a clinical index for nicotine dependence. Daily
nicotine intake was calculated by multiplying the number of
cigarettes per day by nicotine content of cigarette.
The total score for nicotine dependence was calculated by
summing scores on two items that were extracted from
FTND: ‘the number of cigarettes smoked per day’ and ‘time
to the first cigarette of the day’ (Table 1).
In the subpopulation that tried to quit smoking (n¼81),
the degree of withdrawal symptoms was evaluated using a
questionnaire. The degree of withdrawal symptoms was
categorized into three groups: severe, moderate and weak.
Genomic DNA was extracted from blood using the QIAamp
Blood Kit according to the manufacturer’s protocol (Qia-
gen). The genotyping of CYP2A6*4 was carried out by the
PCR-RFLP method, according to the previous report.18The
primers used for the PCR were as follows: forward – CAC
CGA AGT GTT CCC TAT GCT G; reverse – TGT AAA ATG
GGC ATG AAC GCC C. Genomic DNA samples (45ng) were
added to the 25-ml PCR mixtures that consisted of 0.2mM
each primer, PCR Gold Buffer, 2.5mM MgCl2, 0.4mM dNTPs
and 1.25U of AmpliTaq Gold DNA polymerase (Applied
Biosystems). PCR was performed with an initial step at 941C
for 5min, followed by 40 cycles at 951C for 5min, at 561C
for 1min and at 721C for 2min, with a final extension at
721C for 7min. The PCR product was digested with Eco81I.
The digestion patterns were analyzed by electrophoresis
with 2% agarose gel. Mutation allele was identified from the
fragment with 728bp, whereas the wild-type allele was from
that with 789bp.
CYP2A6*9 alleles were genotyped by the allele-specific
PCR method reported previously,5with minor modification.
The primers used for the PCR were as follows: forward – GAT
TCC TCT CCC CTG GAA C, reverse-wild type: GGC TGG
GGT GGT TTG CCT TTA; reverse-mutant type – GGC TGG
GGT GGT TTG CCT TTC. The PCR reaction was performed
in 25ml PCR reaction mixtures containing 45ng genomic
DNA, 0.4mM each primer, PCR Gold Buffer, 2mM MgCl2,
0.2mM each dNTP and 1.25U AmpliTaq Gold DNA
analyzed by the Fagerstrom Test for Nicotine Dependence
Scoring for the degree of nicotine dependence,
Number of cigarettes/day
First cigarette of the day (min)
B¼from XX to XY.
CYP2A6 polymorphisms in smoking cessation
T Kubota et al
The Pharmacogenomics Journal
polymerase. PCR was performed with an initial step at 941C for
5min, followed by 35 cycles at 941C for 30s, at 661C for 30s
and at 721C for 25s, with a final extension at 721C for 7min.
Under these conditions, amplification of DNA fragments
produced single product. The PCR product was detected with
ABI PRISM 7700 Sequence detector (Applied Biosystems) using
fluorescent dye SYBR Green I (Molecular Probes).
Owing to the low frequency, the alleles, except CYP2A6*4
and *9, were defined as CYP2A6*1.
According to the genotypes, subjects were divided into two
groups, high- and low-activity group, as described pre-
In brief, subjects with the *4/*9 and *4/*4
genotypes were considered to have less than 50% of the
enzyme activity of *1/*1 and, therefore, defined as CYP2A6
low-activity group, whereas those with the *1/*1, *1/*9, *1/*4
and *9/*9 genotypes were defined as CYP2A6 high-activity
group. All comparisons were carried out between CYP2A6
high-activity group and CYP2A6 low-activity group. Differ-
ences in the number of cigarettes, daily nicotine intake and
score for nicotine dependence were tested using Mann–
Whitney U-test. The w2test was used to assess the time to the
first cigarette of the day. The frequencies of withdrawal
symptoms were also analyzed with w2test. To assess the
association of the CYP2A6 genotypes with the withdrawal
symptoms, we calculated ORs and their 95% CIs. An
association was reported as statistically significant if the
respective null hypothesis of OR¼1 was rejected at Po0.05
or when the respective 95% CIs did not include the value 1.
Duality of interest
We thank Ms Y Murao for her excellent secretary work. This work is
supported by a Grant-in-Aid for Scientific Research from Ministry of
Education, Science, Sports and Culture of Japan.
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