Impact of CYP2A6 Activity on Nicotine Reinforcement and Cue Reactivity in Daily Smokers

Butler, Kevin, Chenoweth, M, El-Boraie, A, Giratallah, H, Kowalczyk, W, Heishman, S, Tyndale, RF and Le Foll, B (2021) Impact of CYP2A6 Activity on Nicotine Reinforcement and Cue Reactivity in Daily Smokers. Nicotine & Tobacco Research, 23 (10). pp. 1735-1743. ISSN 1469-994X

[img] PDF
ntab064.pdf - Published Version
Restricted to Registered users only
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (449kB)

Search Google Scholar

Abstract

Introduction: Variation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated.
Aims and Methods: CYP2A6 activity was indexed using 3 genetic approaches in 104 daily smokers completing forced choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively. First, smokers were stratified by the presence or absence of reduced/loss-of-function CYP2A6 gene variants (normal vs. reduced metabolizers). As nicotine metabolite ratio (NMR) is a reliable biomarker of CYP2A6 activity, our second and third approaches used additional genetic variants identified in genome-wide association studies of NMR to create a weighted genetic risk score (wGRS) to stratify smokers (fast vs. slow metabolizers) and calculate a wGRS-derived NMR.
Results: Controlling for race and sex, normal metabolizers (vs. reduced) selected a greater proportion of puffs from nicotine-containing cigarettes (vs. denicotinized) on the forced-choice task (p = .031). In confirmatory analyses, wGRS-based stratification (fast vs. slow metabolizers) produced similar findings. Additionally, wGRS-derived NMR, which correlated with actual NMR assessed in a subset of participants (n = 55), was positively associated with the proportion of puffs from nicotine-containing cigarettes controlling for race and sex (p = .015). None of the CYP2A6 indices were associated with tobacco cue-reactivity in minimally deprived smokers.
Conclusions: Findings suggest increased nicotine reinforcement is exhibited by smokers with high CYP2A6 activity, which may contribute to heavier smoking and poorer cessation outcomes previously reported in faster metabolizers.
Implications: CYP2A6 activity is a key determinant of smoking behavior and outcomes. Therefore, these findings support the targeting of CYP2A6 activity, either therapeutically or as a clinically relevant biomarker in a precision medicine approach, for tobacco use disorder treatment.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Psychology > Psychology
Divisions: Faculty of Health Sciences and Wellbeing > School of Psychology
Depositing User: Kevin Butler
Date Deposited: 04 Oct 2021 14:21
Last Modified: 04 Oct 2021 14:21
URI: http://sure.sunderland.ac.uk/id/eprint/14084
ORCID for Kevin Butler: ORCID iD orcid.org/0000-0002-6219-1012

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year