The relationship between the nicotine metabolite ratio and three self-report measures of nicotine dependence across sex and race

Schnoll, Robert A.; George, Tony P.; Hawk, Larry W.; Cinciripini, Paul M.; Wileyto, Paul; Tyndale, Rachel F.

doi:10.1007/s00213-013-3421-1

Cited by 58 publications

(63 citation statements)

References 33 publications

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“…In contrast to the influence of selected variables on NMR described above, variation in CYP2A6 activity, measured by CYP2A6 genotype or NMR, has been previously shown to influence cigarette consumption (i.e., faster metabolizers smoke more heavily) [13, 14, 16, 19]. Thus we were interested in investigating a potential effect of NMR (slow vs. fast nicotine metabolism) on CPD.…”

Section: Resultsmentioning

confidence: 99%

“…Those interesting in participating after meeting eligibility criteria provided a blood sample for NMR determination, collected when participants were smoking as usual. The detailed study protocol, including NMR determination, is described in a previous analysis of NMR and three self-report measures of nicotine dependence in a subset of the trial participants (N=833 of 1807 screened by NMR) [19]. Briefly, cotinine and 3′hydroxycotinine were assessed from whole blood by liquid chromatography-tandem mass spectrometry (LC/MS-MS) using a previously validated method [41, 42].…”

Section: Methodsmentioning

confidence: 99%

“…In addition to cessation, NMR and CYP2A6 genotype are associated with smoking acquisition, the level of cigarette consumption, as well as nicotine dependence [13–19]. Those with slower nicotine metabolism rates, determined via NMR or CYP2A6 genotype, display lower self-reported cigarettes smoked per day [15–17], lower total nicotine intake [20–23], lower nicotine dependence [18, 19], and lower total puff volumes resulting in lower carcinogen exposure [24].…”

Section: Introductionmentioning

confidence: 99%

“…Those with slower nicotine metabolism rates, determined via NMR or CYP2A6 genotype, display lower self-reported cigarettes smoked per day [15–17], lower total nicotine intake [20–23], lower nicotine dependence [18, 19], and lower total puff volumes resulting in lower carcinogen exposure [24]. The relationship between lower NMR and reduced cigarette consumption/nicotine dependence scores may be more pronounced in men than in women [19] and in younger cohorts and smokers not seeking treatment [9, 15]. CYP2A6 genotype is also associated with lung cancer risk; those with reduced activity CYP2A6 genotypes (i.e., slower metabolizers) have a lower risk of developing lung cancer [16, 25–27].…”

Section: Introductionmentioning

confidence: 99%

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Known and Novel Sources of Variability in the Nicotine Metabolite Ratio in a Large Sample of Treatment-Seeking Smokers

Chenoweth

Novalen

Hawk

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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112

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Background The ratio of 3′hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates. Methods NMR as a predictive biomarker of cessation outcomes is being investigated (NCT01314001). In addition to strong CYP2A6-genetic influences on NMR, demographic and hormonal factors alter NMR. Here we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial (N=1672). Results Participants (mean age=45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians vs. African Americans (0.41(0.20) vs. 0.33(0.21); P<0.001), and in females vs. males (0.41(0.22) vs. 0.37(0.20); P<0.001). Among females, birth control pill use (N=17) and hormone replacement therapy (N=14) were associated with 19.5% (P=0.09) and 29.3% (P=0.06) higher mean NMR, respectively, albeit non-significantly. BMI was negatively associated with NMR (Rho=−0.14; P<0.001), while alcohol use (Rho=0.11; P<0.001) and cigarette consumption (Rho=0.12; P<0.001) were positively associated with NMR. NMR was 16% percent lower in mentholated cigarette users (P<0.001). When analyzed together in a linear regression model, these predictors (each ≤2%) accounted for <8% of total NMR variation. Conclusions While these factors significantly affected NMR, they contributed little (together <8%; each ≤2%) to total NMR variation. Impact Thus when using NMR, for example to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Known and Novel Sources of Variability in the Nicotine Metabolite Ratio in a Large Sample of Treatment-Seeking Smokers

Chenoweth

Novalen

Hawk

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

102

112

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“…Written, informed consent was obtained from each subject. Study details were described elsewhere (10, 18). Plasma ( n =35) and urine ( n =35) samples were frozen at −30°C until initial COT and 3HC analysis.…”

Section: Methodsmentioning

confidence: 99%

Nicotine Metabolite Ratio (3-Hydroxycotinine/Cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation

Tanner

Novalen

Jatlow

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Methods Plasma (n=35) and urine (n=35) samples were sent to eight different laboratories, which employed similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Results Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios 0.82–1.16) and were highly correlated (all Pearson r>0.96, P<0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P<0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than in urine, as was observed for NMR. Conclusions Plasma is a very reliable biological source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Impact Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies.

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Pharmacogenetics of Nicotine and Associated Smoking Behaviors

Tanner

Chenoweth

Tyndale

2015

Current Topics in Behavioral Neurosciences

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This chapter summarizes genetic factors that contribute to variation in nicotine pharmacokinetics and nicotine's pharmacological action in the central nervous system (CNS), and how this in turn influences smoking behaviors. Nicotine, the major psychoactive compound in cigarette smoke, is metabolized by a number of enzymes, including CYP2A6, CYP2B6, FMOs, and UGTs, among others. Variation in the genes encoding these enzymes, in particular CYP2A6, can alter the rate of nicotine metabolism and smoking behaviors. Faster nicotine metabolism is associated with higher cigarette consumption and nicotine dependence, as well as lower quit rates. Variation in nicotine's CNS targets and downstream signaling pathways can also contribute to interindividual differences in smoking patterns. Binding of nicotine to neuronal nicotinic acetylcholine receptors (nAChRs) mediates the release of several neurotransmitters including dopamine and serotonin. Genetic variation in nAChRs, and in transporter and enzyme systems that leads to altered CNS levels of dopamine and serotonin, is associated with a number of smoking behaviors. To date, the precise mechanism underpinning many of these findings remains unknown. Considering the complex etiology of nicotine addiction, a more comprehensive approach that assesses the contribution of multiple gene variants, and their interaction with environmental factors, will likely improve personalized therapeutic approaches and increase smoking cessation rates.

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The relationship between the nicotine metabolite ratio and three self-report measures of nicotine dependence across sex and race

Cited by 58 publications

References 33 publications

Known and Novel Sources of Variability in the Nicotine Metabolite Ratio in a Large Sample of Treatment-Seeking Smokers

Known and Novel Sources of Variability in the Nicotine Metabolite Ratio in a Large Sample of Treatment-Seeking Smokers

Nicotine Metabolite Ratio (3-Hydroxycotinine/Cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation

Pharmacogenetics of Nicotine and Associated Smoking Behaviors

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