In Silico Exploration of Foods and Compounds That Modulate Nicotine Metabolism

Background/Objectives: Targeting nicotine metabolism through inhibition of cytochrome P450 2A6 (CYP2A6) has been proposed as a potential strategy for modulating nicotine exposure. CYP2A6 metabolizes nicotine and several clinically relevant compounds, while genetic polymorphisms cause inter-individual variability in nicotine metabolism. Natural products represent accessible and cost-effective sources of compounds with potential relevance to CYP2A6-mediated metabolism. This study aimed to identify naturally occurring food-derived compounds with potential relevance to nicotine metabolism using a combined computational and experimental approach. Methods: A three-step forward/backward workflow was applied. First, CYP2A6-related foods and associated bioactive compounds were identified using FooDisNET and majority voting analysis. Second, selected compounds were experimentally evaluated for inhibitory activity against CYP2A5, the functional orthologue of human CYP2A6, using a murine liver microsome assay. Third, validated inhibitory compounds were traced back to foods and dietary patterns potentially capable of modulating nicotine metabolism. Results: Experimental validation identified four compounds with inhibitory activity against CYP2A5: geraniol, benzaldehyde, 1,8-cineole, and camphor. These compounds were associated with foods including Chinese cinnamon, Mandarin orange (Clementine, Tangerine), Turmeric, Fennel, Corn, Ginger, Artemisia montana, Artemisia capillaris, Akebia trifoliata, Mosla chinensis, Akebia quinata, Elsholtzia ciliata, Artemisia princeps, and Artemisia argyi. Conclusions: These findings identify food-derived compounds with experimentally demonstrated CYP2A5 inhibitory activity and potential relevance to CYP2A6-mediated nicotine metabolism, supporting their further investigation as nutrition-based approaches to modulating nicotine metabolism and smoking reduction or cessation.