Dataset Information

The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.

ABSTRACT:

Background

Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure.

Methods

Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163).

Results

Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males.

Conclusions

In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.

Impact

Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes.

SUBMITTER: Zhu AZ

PROVIDER: S-EPMC3617060 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Publications

The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.

Zhu Andy Z X AZ Renner Caroline C CC Hatsukami Dorothy K DK Swan Gary E GE Lerman Caryn C Benowitz Neal L NL Tyndale Rachel F RF

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20130131 4

<h4>Background</h4>Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure.<h4>Methods</h4>Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex ( ...[more]

PMID: 23371292

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Project description:Background and aimsEvidence 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.DesignPlacebo-controlled randomized smoking cessation trial.SettingAmbulatory care facility in Wisconsin, USA.ParticipantsSmokers (n = 709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy.MeasurementsSurvival 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.FindingsCYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR) = 2.81, 95% confidence interval (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 = 1.97 × 10(-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 (Wald = 7.44, d.f. = 1, P = 0.0064).ConclusionsNicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.

Project description:IntroductionVariation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated.Aims and methodsCYP2A6 activity was indexed using 3 genetic approaches in 104 daily smokers completing forced-choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively. First, smokers were stratified by the presence or absence of reduced/loss-of-function CYP2A6 gene variants (normal vs. reduced metabolizers). As nicotine metabolite ratio (NMR) is a reliable biomarker of CYP2A6 activity, our second and third approaches used additional genetic variants identified in genome-wide association studies of NMR to create a weighted genetic risk score (wGRS) to stratify smokers (fast vs. slow metabolizers) and calculate a wGRS-derived NMR.ResultsControlling for race and sex, normal metabolizers (vs. reduced) selected a greater proportion of puffs from nicotine-containing cigarettes (vs. denicotinized) on the forced-choice task (p = .031). In confirmatory analyses, wGRS-based stratification (fast vs. slow metabolizers) produced similar findings. Additionally, wGRS-derived NMR, which correlated with actual NMR assessed in a subset of participants (n = 55), was positively associated with the proportion of puffs from nicotine-containing cigarettes controlling for race and sex (p = .015). None of the CYP2A6 indices were associated with tobacco cue-reactivity in minimally deprived smokers.ConclusionsFindings suggest increased nicotine reinforcement is exhibited by smokers with high CYP2A6 activity, which may contribute to heavier smoking and poorer cessation outcomes previously reported in faster metabolizers.ImplicationsCYP2A6 activity is a key determinant of smoking behavior and outcomes. Therefore, these findings support the targeting of CYP2A6 activity, either therapeutically or as a clinically relevant biomarker in a precision medicine approach, for tobacco use disorder treatment.

Dataset Information

The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.

Background

Methods

Results

Conclusions

Impact

Publications

The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.

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