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Does sex alter the relationship between CYP2B6 variation, hydroxybupropion concentration, and bupropion-aided smoking cessation in African Americans? A moderated mediation analysis.

BACKGROUND AND AIMS
CYP2B6, a genetically variable enzyme, converts bupropion to its active metabolite hydroxybupropion. CYP2B6 activity and bupropion-aided cessation differ between women and men. The aim of this study was to determine whether genetically normal (vs. reduced) CYP2B6 activity increases bupropion-aided cessation in African American smokers via higher hydroxybupropion concentration, and whether this differs by sex.


DESIGN AND SETTING
Secondary analysis of a smoking cessation clinical trial (NCT00666978).


PARTICIPANTS/CASES
African American light-smokers (≤10 cigarettes/day).


INTERVENTIONS
Participants were treated with bupropion for 7 weeks.


MEASUREMENTS
Participants with detectable bupropion and/or hydroxybupropion concentrations were divided into normal (n=64) and reduced (n=109) CYP2B6 activity groups based on the presence of reduced-function CYP2B6*6 and CYP2B6*18 alleles. Biochemically-verified smoking cessation was assessed at week 3, end-of-treatment (7 weeks), and follow-up (26 weeks).


FINDINGS
Normal (vs. reduced) CYP2B6 activity was associated with increased cessation at week 7, which was mediated by higher hydroxybupropion concentration (odds ratio (OR)=1.25, 95% confidence interval (CI)=1.03, 1.78); this mediation effect persisted at week 26 (OR=1.23, 95% CI=1.02, 1.70). The mediation effect was similar in women (n=116; OR=1.33, 95% CI=1.01, 2.30) and men (n=57; OR=1.33, 95% CI=0.92, 3.87). Moreover, sex did not appear to moderate the mediation effect, although this should be tested in a larger sample.


CONCLUSIONS
In African American light-smokers with verified early bupropion use, genetically normal CYP2B6 activity appears to be indirectly associated with greater smoking cessation success in a relationship mediated by higher hydroxybupropion concentration. The mediating effect of higher hydroxybupropion concentration on smoking cessation persists beyond the active treatment phase and does not appear to differ by sex.