The inhibitory effects of nobiletin on P-glycoprotein and the study of molecular mechanism / 药学学报

ABSTRACT

Nobiletin is a kind of polymethoxyflavonoid with many pharmacological effects, such as antiinflammatory and antioxidation activities. This study was carried out to investigate the inhibitory effects of nobiletin on P-glycoprotein (P-gp) in vitro and in vivo. The molecular mechanism for structure-inhibition relationships of nobiletin with P-gp was investigated. Nobiletin exhibited significant inhibition (IC50=2.21 μmol·L-1) on P-gp in MDR1-MDCKⅡ cells. In the cell toxicity test, the paraquat-treated cell viability was decreased with nobiletin by inhibiting P-gp activity. In the rats PK study, the AUC0-t of digoxin was increased 2.02 folds while the Cmax of digoxin was increased 3.29 folds, when nobiletin was used in the pretreatment of SD rats. Molecular docking analysis elucidated that the formation of Pi-Pi bonds with Phe974 was the key factor for P-gp inhibition. The research findings provide important guideline for prediction of potential interaction between nobiletin and P-gp.