Nicotine metabolism and CYP2A6 activity in a population of black African descent: Impact of gender and light smoking

Mwenifumbo, Jill; Sellers, Edward M.; Tyndale, Rachel F.

doi:10.1016/j.drugalcdep.2006.11.012

Cited by 63 publications

(78 citation statements)

References 54 publications

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“…The association of lower FTND scores with lower NMR is consistent with previous reports suggesting that smokers with slower nicotine metabolism may be less-dependent than those with faster metabolism (Mwenifumbo et al, 2007;Rao et al, 2000;Wassenaar et al, 2011). Although other studies did not find an association between NMR and the level of nicotine dependence (Johnstone et al, 2006), smokers with faster nicotine metabolism reported greater craving for cigarettes following overnight abstinence from smoking.…”

Section: Discussionsupporting

confidence: 89%

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

Sofuoglu

Herman

Nadim

et al. 2012

Neuropsychopharmacol

102

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The ratio of nicotine metabolites (trans-3 0 -hydroxycotinine (3HC) to cotinine) correlates with nicotine clearance. In previous studies, high nicotine metabolite ratio (NMR) predicted poor outcomes for smoking cessation treatment with nicotine patch. The underlying mechanisms that associate NMR with treatment outcomes have not been fully elucidated. A total of 100 smokers were divided into quartiles based on their baseline plasma NMR. Following overnight abstinence, smokers received saline followed by escalating intravenous doses of nicotine (0.5 and 1.0 mg/70 kg) given 30 min apart. The effects of nicotine on subjective, plasma cortisol, heart rate, and systolic and diastolic blood pressure measures were obtained. Smokers in the first NMR quartile (slower metabolizers) had lower Fagerstrom Test for Nicotine Dependence (FTND) scores, suggesting lower levels of dependence. In contrast, smokers in the fourth NMR quartile (faster metabolizers) reported greater craving for cigarettes following overnight abstinence from smoking and reported greater ratings of nicotine-induced good drug effects, drug liking, and wanting more drug. Higher NMR was also associated with greater heart rate increases in response to nicotine. These results suggest that enhanced nicotine reward and cigarette craving may contribute to the poor treatment response in smokers with high NMR. These findings warrant further investigation, especially in treatment-seeking smokers undergoing cessation treatment.

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Section: Discussionsupporting

confidence: 89%

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

Sofuoglu

Herman

Nadim

et al. 2012

Neuropsychopharmacol

102

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“…A comparison of the CYP2A6*23 allele frequencies between ethnic groups, differences in the distribution of the CYP2A6*23 allele in nonsmokers versus smokers, and the Hardy-Weinberg equilibrium were calculated using Fisher's Exact Test. Consistent with previous studies, gender [35] and smoking status [36,37] were found to affect the rate of nicotine metabolism in our population of Black-African descent, as indicated by the 3HC/COT ratio [22]. Thus, the metabolic ratio was adjusted by dividing the value from each individual with the overall mean from their respective group (e.g.…”

Section: Statisticssupporting

confidence: 78%

“…Adults of Black-African descent were recruited from Toronto, Ontario; detailed descriptions of the population and experimental protocol can be found elsewhere [22]. Briefly, male and female current smokers and tried nonsmokers were recruited.…”

Section: Participantsmentioning

confidence: 99%

A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent

Mwenifumbo

Zhao

et al. 2008

Pharmacogenetics and Genomics

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Objectives-CYP2A6 is the main enzyme involved in nicotine metabolism in humans. We have identified a novel allele, CYP2A6*23 (2161C>T, R203C), in individuals of Black-African descent and investigated its impact on enzyme activity and association with smoking status.Methods-Wildtype and variant enzymes containing amino acid changes R203C (CYP2A6*23), R203S (CYP2A6*16) and V365M (CYP2A6*17) were expressed in Escherichia coli. The effect of CYP2A6*23 in vivo was examined in individuals of Black-African descent given 4 mg oral nicotine.Results-CYP2A6*23 occurred at an allele frequency of 2.0% in individuals of Black-African descent (N = 560 alleles, 95% confidence interval 0.8%-3.1%) and was not detected in Caucasians (N = 334 alleles), Chinese (N = 288 alleles) or Japanese (N = 104 alleles). In vitro, CYP2A6.23 had greatly reduced activity towards nicotine C-oxidation similar to CYP2A6.17, as well as reduced coumarin 7-hydroxylation. Conversely, CYP2A6.16 did not differ in activity compared to the wildtype enzyme. The trans-3′-hydroxycotinine to cotinine ratio, a phenotypic measure of CYP2A6 activity in vivo, was lower in CYP2A6*1/*23 and CYP2A6*23/*23 individuals(mean adjusted ratio of 0.60, n = 5) compared to CYP2A6*1/*1 individuals (mean adjusted ratio of 1.21, n = 150) (p < 0.04). CYP2A6*23 trended towards a higher allele frequency in nonsmokers (3.1%, N = 9/286 alleles) compared to smokers (0.7%, N = 2/274 alleles) (p = 0.06).Conclusions-These results suggest the novel CYP2A6*23 allele impairs enzyme function in vitro and in vivo and trends toward an association with lower risk of smoking.

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“…This finding might have clinical implications in patients treated with drugs metabolized by CYP2A6, such as halothane, valproic acid, and disulfiram [1,29]. Most of the previous studies observed sex differences in CYP2A6 activity [4,[7][8][9][10]. Benowitz et al [7], using plasma trans-3′-hydroxycotinine/cotinine ratio, reported faster nicotine metabolism in premenopausal (but not postmenopausal) women compared to men.…”

Section: Discussionmentioning

confidence: 93%

“…Previous studies, using nicotine and cotinine as probes, showed an inhibitory effect of cigarette smoking on CYP2A6 enzyme activity [5,6]. Sex differences have been observed as well [4,[7][8][9][10], but the findings were not always consistent [11,12]. Nevertheless, the major cause for the observed variability in enzyme activity seems to be genetic polymorphisms of the CYP2A6 gene [1].…”

Section: Introductionmentioning

confidence: 99%

In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population

Djordjević

Carrillo

Gervasini

et al. 2010

Eur J Clin Pharmacol

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Purpose The main aim of the study was to investigate the distribution of cytochrome P450 2A6 (CYP2A6) and xanthine oxidase (XO) enzyme activities in the Serbian population. Secondly, we tested the influence of genetics (CYP2A6 polymorphism), sex, and cigarette smoking on both enzymes. Methods One hundred forty healthy Serbian volunteers were genotyped for common CYP2A6 alleles. In 100 of them, CYP2A6 and XO activities were determined by the urinary 17U/17X and 1U/(1U+1X) ratios, respectively, after oral administration of 100 mg caffeine as a probe. Results A 21-fold variation in the 17U/17X ratio was observed (range: 0.49-10.28, mean=1.65, 95% CI: 1.49-1.83). The urinary 1U/(1U+1X) ratios displayed four-fold variation, ranging from 0.17 to 0.71 (mean=0.43, 95% CI: 0.41-0.45). CYP2A6 alleles *1A, *1B1, *9, *4 and *1B1x2 were found with frequencies of 0.579, 0.307, 0.082, 0.029, and 0.004 respectively. CYP2A6*5 was not detected. CYP2A6 genotype influenced interindividual variability in CYP2A6 enzyme activity (P=0.04). Cigarette smoking inhibited CYP2A6 enzyme activity (P=0.02), but had no effect on activity of XO (P=0.16).There was no significant difference between men and women in terms of CYP2A6 or XO activity. Conclusions Serbs displayed interindividual variations in CYP2A6 activity. CYP2A6 genotype and cigarette smoking, but not sex, influenced CYP2A6 enzyme activity. Unimodal distribution of XO enzyme activity in Serbs implies the absence of subjects with low enzyme activity in this population. XO activity is not influenced by sex or cigarette smoking.

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Nicotine metabolism and CYP2A6 activity in a population of black African descent: Impact of gender and light smoking

Cited by 63 publications

References 54 publications

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent

In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population

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