Inhibiting CYP2A5 enzyme in mice decreases circulating cotinine after nicotine administration and increases dopamine in the brain

Smoking is a public health concern, and smoking cessation methods such as nicotine replacement therapy (NRT) are often ineffective partly because they are not personalized. Smoking behavior is related to polymorphisms of the nicotine-metabolizing enzyme P450 2A6. Accordingly, fast metabolizers are nicotine-dependent, smoke more cigarettes and have lower quitting rates compared to slow metabolizers. Thus, inhibiting the nicotine-metabolizing enzyme and prolonging the presence of nicotine in the blood could lead to enhanced NRT and/or fewer cigarettes smoked.In this study, we examined whether Ginkgo biloba (GB), its main constituent quercetin, and 8-methoxypsoralen (8-MOP) can inhibit nicotine metabolism in vivo in mice. We administered nicotine to mice in the presence or absence of the test articles and measured serum cotinine levels, brain dopamine levels and liver CYP2A5 activity.Our results indicate that 8-MOP can inhibit nicotine metabolism in vivo by 55% and increase dopamine in the brain. Chronic administration of GB and quercetin did not detectably inhibit nicotine metabolism, however, GB increased dopamine in the brain. Our results suggest that supplements or drugs that can inhibit nicotine metabolism sufficiently may help smokers reduce the number of cigarettes smoked by prolonging the presence of nicotine in the blood and dopamine in the brain.