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

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.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 flavonoids and previously isolated flavonoids from Vernonia cinerea and Pluchea indica against both enzymes.Kaempferol could inhibit CYP2A6 with Kic value of 1.77 ± 0.47 µM while inhibit CYP2A13 with Kic value of 0.12 ± 0.01 µM. Myricetin could inhibit CYP2A6 with Kic value of 4.06 ± 0.52 µM while inhibit CYP2A13 with Kic value of 1.88 ± 0.03 µM.Molecular docking indicated that CYP2A13 enzyme has 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.

Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from Pluchea indica and Vernonia cinerea.

The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1-4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5-8 from V. cinerea, and acetylenic thiophenes 9-11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic KI values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32-15.4 and 0.92-8.67 µM, respectively, while those of thiophenes were 0.11-1.01 and 0.67-0.97 µM, respectively.