Pharmacogenetics of Nicotine Metabolism in Twins: Methods and Procedures

Swan, Gary E.; Benowitz, Neal L.; Jacob, Peyton; Lessov, Christina N.; Tyndale, Rachel F.; Wilhelmsen, Kirk C.; Krasnow, Ruth E.; McElroy, Mary; Moore, Sharyn E.; Wambach, Michelle

doi:10.1375/1369052042335269

Cited by 38 publications

(42 citation statements)

References 57 publications

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“…To investigate the association among CYP2A6 genotype, plasma measures, and metabolite ratios, participants were classified into genotype groups, based on the known in vivo and/or in vitro effect on enzyme function of each CYP2A6 allele (9,(38)(39)(40). Based on our present findings for nicotine and those reported previously for coumarin (29), participants who were heterozygous for the CYP2A6*12A variant were grouped among those expected to have 60% to 70% remaining activity.…”

Section: Methodsmentioning

confidence: 99%

CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking

Malaiyandi

Goodz

Sellers³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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CYP2A6 inactivates nicotine to cotinine and cotinine to 3-hydroxycotinine. We investigated which of plasma nicotine and metabolites were most related to CYP2A6 genotype and smoking levels. We assessed demographic and smoking histories in 152 Caucasian ad libitum smokers, measured breath carbon monoxide (CO) levels, and determined plasma nicotine, cotinine, and 3-hydroxycotinine by highperformance liquid chromatography and CYP2A6 genotypes by PCR. Cigarettes per day was most closely related to CO (r = 0.60, P < 0.001) followed by plasma cotinine (r = 0.53, P < 0.001), whereas plasma cotinine was most strongly correlated with CO levels (r = 0.74, P < 0.001), confirming that cotinine is a good indicator of smoking levels; this was not limited by CYP2A6 variants. 3-Hydroxycotinine/cotinine is reported to be a good marker of CYP2A6 activity, and we found that the 3-hydroxycotinine/(cotinine + nicotine) ratio was most correlated with CYP2A6 genotype (r = 0.38, P < 0.001). Inclusion of the CYP2A6*12A allele strengthened the correlation (r = 0.46, P < 0.001), suggesting that the identification of novel alleles will continue to improve this relationship. Nicotine metabolism is slower in smokers, and we have shown that CYP2A6 is reduced by nicotine treatment in monkeys. Here, we found that plasma nicotine levels were inversely correlated with CYP2A6 activity (3-hydroxycotinine/cotinine, r = À0.41, P < 0.001) among those without CYP2A6 variants, suggesting a reduction in metabolism with higher nicotine levels. Together, these findings (a) confirm the use of plasma cotinine and CO as indicators of Caucasians' smoking levels, and that this is not limited by CYP2A6 genetic variation; (b) indicate that 3-hydroxycotinine/cotinine and 3-hydroxycotinine/(cotinine + nicotine) are moderately good indicators of the CYP2A6 genotype; and (c) support that nicotine exposure may reduce its own metabolism. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1812 -9)

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Section: Methodsmentioning

confidence: 99%

CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking

Malaiyandi

Goodz

Sellers³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Because the study procedures could be seriously confounded or could lead to adverse events for the participants by the presence of the conditions described above, a three-tiered screening procedure (telephone, in-person, and in-hospital) was employed (described more completely elsewhere; ref. 22).…”

Section: Methodsmentioning

confidence: 99%

“…In previous reports, we presented the methodology and results of a large twin study of nicotine metabolism (22)(23)(24)(25)(26). Before, during, and after the controlled infusion of deuteriumlabeled nicotine and cotinine, participants' heart rate was measured at regular intervals.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Environmental Sources of Variation in Heart Rate Response to Infused Nicotine in Twins

Swan

Lessov‐Schlaggar

Krasnow

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The heart rate response to nicotine may be an important component of the process leading to dependence. The present study is the first to determine the extent to which genetic and environmental sources play a role in various components of the heart rate response. One hundred and ten monozygotic and 29 dizygotic twin pairs received an i.v. infusion of nicotine and cotinine over 30 min. Before, during, and for 30 min after infusion, heart rate was measured via an electronic monitor. The clearance of nicotine was determined as a measure of the rate of nicotine metabolism. Average resting heart rate before infusion was 64.7 beats per minutes (bpm), and at the termination of infusion, heart rate had increased to an average of 72.7 bpm. At 30 min after infusion, heart rate had decreased to 67.5 bpm. Age, current smoking status, body mass index, and nicotine clearance were associated significantly with heart rate levels over the full 60 min of measurement. After adjustment for several covariates, including dose of administered nicotine and rate of nicotine clearance, the variance in several characteristics of the heart rate response curve was examined for the relative contribution from genetic and environmental sources. In the total sample, as much as 30.3% of the variance in the acceleration of heart rate was due to additive genetic sources. In nonsmokers, 34.8% and 31.0% of variance in the acceleration and deceleration of heart rate, respectively, was due to genetic sources. Heart rate acceleration and deceleration may be a reflection of central nervous system responsiveness to nicotine. The contribution from genetic sources to heart rate response characteristics should be investigated further as a potential endophenotype for use in genetic studies of nicotine dependence. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1057 -64)

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“…We assessed association of rs316019 with measures of nicotine renal clearance in two laboratory studies of nicotine and cotinine metabolism. 54,55 We performed genotype QC in SAS Genetics Version 9.2 (Cary), phenotype imputation and phenotype genoytpe regression analyses using STATA 12.0 (StataCorp), principal components analyses using EIGENSTRAT 56 and GCTA, 57 LD analyses using Haploview 58 and SNAP, 59 haplotype and diplotype analyses using PHASE, 60 and power analyses using Quanto. 61 All tests were two-sided, and alpha for all tests was 0.05.…”

Section: Post-hoc Analyses Performedmentioning

confidence: 99%

Organic Cation Transporter Variation and Response to Smoking Cessation Therapies

Bergen

Javitz

Krasnow

et al. 2014

Nicotine & Tobacco Research

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Pharmacogenetics of Nicotine Metabolism in Twins: Methods and Procedures

Cited by 38 publications

References 57 publications

CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking

CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking

Genetic and Environmental Sources of Variation in Heart Rate Response to Infused Nicotine in Twins

Organic Cation Transporter Variation and Response to Smoking Cessation Therapies

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