Structure-activity relationship and in vitro inhibition of human CYP2A6 and CYP2A13 by flavonoids.

1. Cigarette smoking is one of the major risk factors of various diseases including respiratory diseases and lung cancer. While the liver-specific CYP2A6 is associated with the nicotine clearance and smoking addiction, the metabolic activation of the tobacco-specific nitrosamine by lung specific CYP2A13 can lead to lung tumorigenesis. 2. It has been reported that inhibition of CYP2A6 and CYP2A13 enzymes by flavonoids constituents could be an aids in smoking cessation. This study demonstrates the inhibition activity of kaempferol and myricetin and the structure-function relationship of these two flavonoid and previously isolated flavonoids from Vernonia cinerea and Pluchea indica against both enzymes. 3. Kaempferol could inhibit CYP2A6 with K_ic value of 1.77 ± 0.47 µM while inhibit CYP2A13 with K_ic value of 0.12 ± 0.01 µM. Myricetin could inhibit CYP2A6 with K_ic value of 4.06 ± 0.52 µM while inhibit CYP2A13 with K_ic value of 1.88 ± 0.03 µM. 4. Molecular docking indicated that CYP2A13 enzyme have strong hydrophobic interaction with ring B of flavonoids compared to CYP2A6 enzyme. The presence of the hydroxyl group at C3 position of ring C and the hydroxyl group at C5' of ring B affected inhibitory activity on both enzymes.