<i>CYP2B6</i> Genotype Does Not Alter Nicotine Metabolism, Plasma Levels, or Abstinence with Nicotine Replacement Therapy

Lee, AM; Jepson, Christopher; Shields, Peter G.; Benowitz, Neal L.; Lerman, Caryn; Tyndale, Rachel F.

doi:10.1158/1055-9965.epi-07-0188

Cited by 44 publications

(35 citation statements)

References 12 publications

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“…Future investigations will clarify whether dependent adolescent smokers, even at comparatively lower levels of cigarette consumption versus adults, titrate their level of nicotine intake according to their rate of nicotine metabolism in order to maintain desirable levels (Ashton et al, 1979;Hill and Marquardt, 1980), with CYP2A6 slow metabolizers needing to smoke fewer cigarettes to achieve these levels. In contrast to CYP2A6, variation in CYP2B6 does not substantially alter the rate of peripheral nicotine metabolism or cigarette consumption (Lee et al, 2007b); we also showed a lack of significant association between CYP2B6 and adolescent cigarette consumption.…”

Section: Discussioncontrasting

confidence: 58%

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

Chenoweth

Sylvestre

Contreras

et al. 2016

Drug and Alcohol Dependence

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Background-Smoking is influenced by genetic factors including variation in CYP2A6 and CYP2B6, which encode nicotine-metabolizing enzymes. In early adolescence, CYP2A6 slow nicotine metabolism was associated with higher dependence acquisition, but reduced cigarette consumption. Here we extend this work by examining associations of CYP2A6 and CYP2B6 with tobacco dependence acquisition in a larger sample of smokers followed throughout adolescence.Methods-White participants from the Nicotine Dependence in Teens cohort that had ever inhaled (n=421) were followed frequently from age 12-18 years. Cox's proportional hazards models compared the risk of ICD-10 tobacco dependence acquisition (score 3+) for CYP2A6 and CYP2B6 metabolism groups. Early smoking experiences, as well as amount smoked at end of follow-up, was also computed. At age 24 (N=162), we assessed concordance between selfreported cigarette consumption and salivary cotinine.Results-In those who initiated inhalation during follow-up, CYP2A6 slow (vs. normal) metabolizers were at greater risk of dependence (hazards ratio (HR)=2.3; 95% CI=1.1, 4.8); CYP2B6 slow (vs. normal) metabolizers had non-significantly greater risk (HR=1.5; 95% CI=0.8, 2.6). Variation in CYP2A6 or CYP2B6 was not significantly associated with early smoking symptoms or cigarette consumption at end of follow-up. At age 24, neither gene was significantly associated with dependence status. Self-reported consumption was associated with salivary cotinine, a biomarker of tobacco exposure, acquired at age 24 (B=0.37; P<0.001). CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptConclusions-Our findings extend previous work indicating that slow nicotine metabolism mediated by CYP2A6, and perhaps CYP2B6, increases risk for tobacco dependence throughout adolescence.

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Section: Discussioncontrasting

confidence: 58%

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

Chenoweth

Sylvestre

Contreras

et al. 2016

Drug and Alcohol Dependence

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“…Most research on the role of genetic variation on smoking cessation pharmacotherapy has been directed to the two most widely accepted and licensed forms of smoking cessation therapy: nicotine replacement therapy (NRT) [111,[124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140] and the antidepressant bupropion (Zyban1) [129,137,[141][142][143][144][145][146][147][148][149].…”

Section: Influence Of Genetic Variations On Smoking Cessation Treatmentmentioning

confidence: 99%

“…Thirdly, smokers who have increased activity variants in the m-opioid receptor (MOR) may have better success with the higher levels of nicotine delivered by TN compared with the lower levels of nicotine from NS [125,136,138], possibly only in combination with variants in MOR-interacting proteins [138]. Fourthly, an increased nicotine metabolism (determined primarily by CYP2A6 genotype but probably not by CYP2B6 genotype) lowers quit rates with TN [128,130,135]. Fifthly, variants in 5-HTT do not seem to influence the response to NRT [131,132].…”

Section: Influence Of Genetic Variations On Smoking Cessation Treatmentmentioning

confidence: 99%

Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?

Quaak¹,

Schayck²,

Knaapen³

et al. 2009

European Respiratory Journal

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Tobacco smoking continues to be the largest preventable cause of premature morbidity and mortality throughout the world, including chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease. Although most smokers are highly motivated to quit and many smoking cessation therapies are available, cessation rates remain very low.Recent research strongly suggests that variation in genetic background is an important determinant of smoking behaviour and addiction. Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, it is likely that assessment of genetic background could be a promising tool to guide selection of the most effective cessation treatment for an individual smoker. Recently, it has been shown that genetic variants in the dopaminergic system, opioid receptors, the bupropion-metabolising enzyme CYP2B6 and the nicotine-metabolising enzyme CYP2A6 may play an important role in predicting smoking cessation responses to nicotine replacement therapy and bupropion treatment. Despite the progress that has been made, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

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“…The contribution of CYP2B6 to nicotine clearance in humans is believed to be relatively small and influenced by the activity of the more dominant CYP2A6 (Yamanaka et al, 2004;Dicke et al, 2005;Al Koudsi and Tyndale, 2010). The impact of CYP2B6 genetic polymorphisms on nicotine clearance has been examined in a number of studies, yielding positive results in some (Johnstone et al, 2006;Ring et al, 2007;Bloom et al, 2013), but not in others (Lee et al, 2007;Binnington et al, 2012). Here, we have provided in vivo proof-ofprinciple in the mouse model that CYP2B6 could make a significant contribution to nicotine oxidation and systemic clearance, particularly at the induced level, albeit in the absence of the more dominant mouse CYP2A5 and CYP2B enzymes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

Liu

et al. 2014

Drug Metab Dispos

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The aim of this study was to further characterize the expression and function of human CYP2B6 in a recently generated CYP2A13/ 2B6/2F1-transgenic (TG) mouse model, in which CYP2B6 is expressed selectively in the liver. The inducibility of CYP2B6 by phenobarbital (PB) and dexamethasone (DEX), known inducers of CYP2B6 in human liver, was examined in the TG mice, as well as in TG/Cyp2abfgs-null (or "CYP2B6-humanized") mice. Hepatic expression of CYP2B6 mRNA and protein was greatly induced by PB or DEX treatment in both TG and TG/Cyp2abfgs-null mice. Function of the transgenic CYP2B6 was first studied using bupropion as a probe substrate. In PB-treated mice, the rates of hepatic microsomal hydroxybupropion formation (at 50 mM bupropion) were >4-fold higher in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice (for both male and female mice); the rate difference was accompanied by a 5-fold higher catalytic efficiency in the TG/Cyp2abfgs-null mice and was abolished by an antibody to CYP2B6. The ability of CYP2B6 to metabolize nicotine was then examined, both in vitro and in vivo. The rates of hepatic microsomal cotinine formation from nicotine were significantly higher in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice, pretreated with PB or DEX. Furthermore, systemic nicotine metabolism was faster in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice. Thus, the transgenic CYP2B6 was inducible and functional, and, in the absence of mouse CYP2A and CYP2B enzymes, it contributed to nicotine metabolism in vivo. The CYP2B6-humanized mouse will be valuable for studies on in vivo roles of hepatic CYP2B6 in xenobiotic metabolism and toxicity.

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CYP2B6 Genotype Does Not Alter Nicotine Metabolism, Plasma Levels, or Abstinence with Nicotine Replacement Therapy

Cited by 44 publications

References 12 publications

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?

Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

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