Populations of Black-African descent have slower rates of nicotine and cotinine metabolism, smoke fewer cigarettes (~10 cigarettes/day), and have higher incidences of tobacco-related illnesses compared to Caucasians. Cytochrome P450 2A6 (CYP2A6) is the main enzyme involved in the metabolism of nicotine and its proximal metabolite cotinine, as well as tobacco-specific nitrosamines. Genetic polymorphisms in CYP2A6 contribute to the large variability observed in rates of nicotine metabolism. Reduced CYP2A6 activity has been associated with fewer cigarettes smoked, higher quit rates, and lower lung cancer risk in predominantly moderate to heavy-smoking (~20–30 cigarettes/day) Caucasians. CYP2A6 genetic variants and their impact on smoking behaviours have not been well studied among individuals of Black-African descent. The main objectives herein were to identify and characterize new CYP2A6 variants that may explain the slower rates of metabolism, and determine whether CYP2A6 variation is a predictor of smoking phenotypes in this population. Furthermore, we examined whether previously validated biomarkers of tobacco exposure have limitations among individuals of Black-African descent given their low and sporadic smoking patterns. A new CYP2A6 variant (CYP2A6*23) was found in individuals of Black-African descent recruited for a nicotine pharmacogenetic-pharmacokinetic study. CYP2A6*23 reduced activity towards nicotine and coumarin in vitro and was associated with slower rates of CYP2A6 kinetics in vivo. In a clinical trial of African-American light smokers, CYP2A6 slow metabolizers were more successful at smoking cessation compared to normal metabolizers, although no differences in cigarette consumption were found. Two common biochemical markers of tobacco smoke exposure, cotinine and exhaled carbon monoxide, were weakly correlated with self-reported cigarette consumption. These biomarkers were not substantially affected by variables previously shown to alter amount smoked and/or rates of cotinine metabolism such as gender, age, body mass index or smoking menthol cigarettes. However, CYP2A6 slow metabolizers had significantly higher cotinine without smoking more cigarettes. Identification and characterization of novel variants adds to our understanding of nicotine pharmacokinetic differences between racial/ethnic minority groups and improves accuracy of CYP2A6 genotype groupings for genetic association studies. Furthermore, better insight into the biological factors associated with smoking behaviours will aid in the development of more efficacious targeted treatments for this understudied population.

Populations of Black-African descent have slower rates of nicotine and cotinine metabolism, smoke fewer cigarettes (~10 cigarettes/day), and have higher incidences of tobacco-related illnesses compared to Caucasians. Cytochrome P450 2A6 (CYP2A6) is the main enzyme involved in the metabolism of nicotine and its proximal metabolite cotinine, as well as tobacco-specific nitrosamines. Genetic polymorphisms in CYP2A6 contribute to the large variability observed in rates of nicotine metabolism. Reduced CYP2A6 activity has been associated with fewer cigarettes smoked, higher quit rates, and lower lung cancer risk in predominantly moderate to heavy-smoking (~20–30 cigarettes/day) Caucasians. CYP2A6 genetic variants and their impact on smoking behaviours have not been well studied among individuals of Black-African descent. The main objectives herein were to identify and characterize new CYP2A6 variants that may explain the slower rates of metabolism, and determine whether CYP2A6 variation is a predictor of smoking phenotypes in this population. Furthermore, we examined whether previously validated biomarkers of tobacco exposure have limitations among individuals of Black-African descent given their low and sporadic smoking patterns. A new CYP2A6 variant (CYP2A6*23) was found in individuals of Black-African descent recruited for a nicotine pharmacogenetic-pharmacokinetic study. CYP2A6*23 reduced activity towards nicotine and coumarin in vitro and was associated with slower rates of CYP2A6 kinetics in vivo. In a clinical trial of African-American light smokers, CYP2A6 slow metabolizers were more successful at smoking cessation compared to normal metabolizers, although no differences in cigarette consumption were found. Two common biochemical markers of tobacco smoke exposure, cotinine and exhaled carbon monoxide, were weakly correlated with self-reported cigarette consumption. These biomarkers were not substantially affected by variables previously shown to alter amount smoked and/or rates of cotinine metabolism such as gender, age, body mass index or smoking menthol cigarettes. However, CYP2A6 slow metabolizers had significantly higher cotinine without smoking more cigarettes. Identification and characterization of novel variants adds to our understanding of nicotine pharmacokinetic differences between racial/ethnic minority groups and improves accuracy of CYP2A6 genotype groupings for genetic association studies. Furthermore, better insight into the biological factors associated with smoking behaviours will aid in the development of more efficacious targeted treatments for this understudied population.

Nicotine is the primary substance in tobacco causing addiction. In humans the majority (70-80%) of nicotine is inactivated to cotinine in a reaction predominantly catalyzed by CYP2A6 (80-90%), with a minor possible role for CYP2B6. Substantial interindividual variability is observed in the rate of nicotine’s inactivation to cotinine and this variation contributes to differences in smoking behaviors (e.g. cigarette consumption). Twin studies suggest an important genetic contribution to the variability in nicotine metabolism. However in 2004, genetic variation in CYP2A6 and CYP2B6 accounted for only a small portion of the variability suggesting gaps in our knowledge. Our objective was to identify additional genetic and non-genetic sources of variability in CYP2A6 expression/activity, CYP2B6 expression, and nicotine to cotinine metabolism in vivo and/or in vitro. Participants included individuals from different world populations phenotyped for CYP2A6 activity either following oral nicotine administration or using metabolite ratios derived from baseline smoking. Genotyping and sequencing were utilized to identify and characterize multiple new CYP2A6 alleles. In total 17 novel CYP2A6 alleles were identified, many of which were found predominantly among individuals of black African descent and exhibited lower CYP2A6 activity. In addition, human livers were assessed for CYP2A6 and CYP2B6 expression and nicotine to cotinine metabolism. The mechanisms underlying the lower CYP2A6 activity associated with some of the variant CYP2A6 alleles included either a reduction in hepatic CYP2A6 protein expression, an alteration of CYP2A6’s structural property, or a combination of both. DNA methylation was not associated with altered hepatic CYP2A6 expression/activity. Livers from female donors were associated with higher CYP2A6 and CYP2B6 protein expression compared to male livers, while age did not influence the expression of either CYP. Finally, CYP2B6 and its prevalent altered function genetic variant (CYP2B6*6) did not influence nicotine to cotinine metabolism. Identification of factors that contribute to the variability in CYP2A6 and nicotine metabolism is important to improve future association studies between CYP2A6 genotype, nicotine metabolism, and smoking behaviors. In addition, this information could provide the potential to personalize therapy in order to improve the clinical efficacy of nicotine, particularly as a smoking cessation aid.

Nicotine is the primary substance in tobacco causing addiction. In humans the majority (70-80%) of nicotine is inactivated to cotinine in a reaction predominantly catalyzed by CYP2A6 (80-90%), with a minor possible role for CYP2B6. Substantial interindividual variability is observed in the rate of nicotine’s inactivation to cotinine and this variation contributes to differences in smoking behaviors (e.g. cigarette consumption). Twin studies suggest an important genetic contribution to the variability in nicotine metabolism. However in 2004, genetic variation in CYP2A6 and CYP2B6 accounted for only a small portion of the variability suggesting gaps in our knowledge. Our objective was to identify additional genetic and non-genetic sources of variability in CYP2A6 expression/activity, CYP2B6 expression, and nicotine to cotinine metabolism in vivo and/or in vitro. Participants included individuals from different world populations phenotyped for CYP2A6 activity either following oral nicotine administration or using metabolite ratios derived from baseline smoking. Genotyping and sequencing were utilized to identify and characterize multiple new CYP2A6 alleles. In total 17 novel CYP2A6 alleles were identified, many of which were found predominantly among individuals of black African descent and exhibited lower CYP2A6 activity. In addition, human livers were assessed for CYP2A6 and CYP2B6 expression and nicotine to cotinine metabolism. The mechanisms underlying the lower CYP2A6 activity associated with some of the variant CYP2A6 alleles included either a reduction in hepatic CYP2A6 protein expression, an alteration of CYP2A6’s structural property, or a combination of both. DNA methylation was not associated with altered hepatic CYP2A6 expression/activity. Livers from female donors were associated with higher CYP2A6 and CYP2B6 protein expression compared to male livers, while age did not influence the expression of either CYP. Finally, CYP2B6 and its prevalent altered function genetic variant (CYP2B6*6) did not influence nicotine to cotinine metabolism. Identification of factors that contribute to the variability in CYP2A6 and nicotine metabolism is important to improve future association studies between CYP2A6 genotype, nicotine metabolism, and smoking behaviors. In addition, this information could provide the potential to personalize therapy in order to improve the clinical efficacy of nicotine, particularly as a smoking cessation aid.

No description available.

We investigated the efficacy of standard (8-week nicotine, 16-week placebo) vs extended (24-week nicotine) patch therapy for smoking cessation, and the effect of slow nicotine metabolism, indicated by CYP2A6 reduced metabolizer (RM) genotype or low 3-hydroxycotinine/cotinine ratio (3HC/COT), on abstinence. RM versus normal genotype predicted lower 3HC/COT. Extended vs standard treatment produced higher abstinence at 24 weeks (32% vs 20%), but not at 52 weeks (both 14%). Low 3HC/COT and RM genotype predicted higher abstinence on extended versus standard treatment at 24 (47% vs 25%, 38% vs 17%) and 28 weeks (34% vs 19%, 23% vs 11%), while high 3HC/COT or normal genotype did not. Within extended treatment, low versus high 3HC/COT predicted higher abstinence at 8 (48% vs 29%), 24 (47% vs 25%), and 28 weeks (34% vs 16%), with similar trends for the genotype effect. Overall, extending nicotine treatment increased abstinence during therapy, particularly for slow metabolizers.

We investigated the efficacy of standard (8-week nicotine, 16-week placebo) vs extended (24-week nicotine) patch therapy for smoking cessation, and the effect of slow nicotine metabolism, indicated by CYP2A6 reduced metabolizer (RM) genotype or low 3-hydroxycotinine/cotinine ratio (3HC/COT), on abstinence. RM versus normal genotype predicted lower 3HC/COT. Extended vs standard treatment produced higher abstinence at 24 weeks (32% vs 20%), but not at 52 weeks (both 14%). Low 3HC/COT and RM genotype predicted higher abstinence on extended versus standard treatment at 24 (47% vs 25%, 38% vs 17%) and 28 weeks (34% vs 19%, 23% vs 11%), while high 3HC/COT or normal genotype did not. Within extended treatment, low versus high 3HC/COT predicted higher abstinence at 8 (48% vs 29%), 24 (47% vs 25%), and 28 weeks (34% vs 16%), with similar trends for the genotype effect. Overall, extending nicotine treatment increased abstinence during therapy, particularly for slow metabolizers.

No description available.

The impact of CYP2A6 and CYP2B6 genetic variation on nicotine metabolism, tobacco use behaviours, and nicotine biomarkers was investigated in a group of Alaska Natives (n = 400). CYP2A6 and CYP2B6 allele frequencies were unique and associations of CYP2A6 genotype and CYP2A6 activity (plasma and urine trans 3’-hydroxycotinine/cotinine (3HC/COT) ratios) were robust. Notably, this population possessed a more rapid rate of CYP2A6 activity (higher plasma 3HC/COT) when compared to CYP2A6 wild-type individuals in other ethnic groups (ANOVA P < 0.001). Also demonstrated was a significant difference in urine total nicotine equivalents by CYP2A6 activity median split (t-test P < 0.01), the first evidence of nicotine titration by CYP2A6 activity within a light smoking population. Overall, this population possessed a distinctive pattern of CYP2A6 and CYP2B6 variant frequencies and a faster rate of nicotine metabolism, which may in part explain higher levels of tobacco use prevalence and tobacco-related disease risk.

The impact of CYP2A6 and CYP2B6 genetic variation on nicotine metabolism, tobacco use behaviours, and nicotine biomarkers was investigated in a group of Alaska Natives (n = 400). CYP2A6 and CYP2B6 allele frequencies were unique and associations of CYP2A6 genotype and CYP2A6 activity (plasma and urine trans 3’-hydroxycotinine/cotinine (3HC/COT) ratios) were robust. Notably, this population possessed a more rapid rate of CYP2A6 activity (higher plasma 3HC/COT) when compared to CYP2A6 wild-type individuals in other ethnic groups (ANOVA P < 0.001). Also demonstrated was a significant difference in urine total nicotine equivalents by CYP2A6 activity median split (t-test P < 0.01), the first evidence of nicotine titration by CYP2A6 activity within a light smoking population. Overall, this population possessed a distinctive pattern of CYP2A6 and CYP2B6 variant frequencies and a faster rate of nicotine metabolism, which may in part explain higher levels of tobacco use prevalence and tobacco-related disease risk.