Nicotine
is the primary psychoactive chemical in both traditional
and electronic cigarettes (e-cigarettes). Nicotine levels in both
traditional cigarettes and e-cigarettes are an important concern for
public health. Nicotine exposure due to e-cigarette use is of importance
primarily due to the addictive potential of nicotine, but there is
also concern for nicotine poisoning in e-cigarette users. Nicotine
concentrations in e-liquids vary widely. Additionally, there is significant
genetic variability in the rate of metabolism of nicotine due to polymorphisms
of CYP2A6, the enzyme responsible for the metabolism of approximately
80% of nicotine. Recent studies have shown CYP2A6 activity is also
reduced by aromatic aldehydes such as those added to e-liquids as
flavoring agents, which may increase nicotine serum concentrations.
However, the impacts of flavored e-liquids on CYP2A6 activity are
unknown. In this study, we investigated the impact of three flavored
e-liquids on microsomal recombinant CYP2A6. Microsomal recombinant
CYP2A6 was challenged at e-liquid concentrations ranging up to 0.125%
(v/v) and monitored for metabolic activity using a probe molecule
approach. Two e-liquids exhibited dose-dependent inhibition of CYP2A6
activity. Mass spectrometry was conducted to identify flavoring agents
in flavored e-liquids that inhibited CYP2A6. Microsomal recombinant
CYP2A6 was subsequently exposed to flavoring agents at concentrations
ranging from 0.03 μM to 500 μM. Cinnamaldehyde and benzaldehyde
were found to be the most potent inhibitors of microsomal CYP2A6 of
the flavoring agents tested, with identified IC50 values
of 1.1 μM and 3.0 μM, respectively. These data indicate
certain aromatic aldehyde flavoring agents are potent inhibitors of
CYP2A6, which may reduce nicotine metabolism in vivo. These findings
indicate an urgent need to evaluate the effects of flavoring agents
in e-cigarette liquids on the pharmacokinetics of nicotine in vivo.
