Abstract

The polyisoprenylated benzophenones, guttiferone K and oblongifolin C were found in several Garcinia plants (family Clusiaceae) and exhibited remarkable antitumor activity. However, their effect on P-glycoprotein (P-gp) function has never been investigated. This study aimed to assess the effect of guttiferone K and oblongifolin C on P-gp function in Caco-2 cells using the calcein-AM uptake assay to measure the accumulation of the fluorescent calcein, a substrate of P-gp, within the cells under pre/co-treatment condition. Verapamil, a well-known P-gp substrate/ inhibitor, was employed as a positive control. Both compounds could inhibit P-gp function, causing increased cellular accumulation of calcein. Their roles as both P-gp substrates and P-gp inhibitors were predicted from their chemical structures through SwissADME and admetSAR programs. Furthermore, the effect of these two benzophenones on the ATP-binding region at nucleotide-binding domain 1 (NBD1) of P-gp was investigated by a molecular docking study. They could bind more favourably than verapamil to the ATP-binding region within NBD1 of P-gp. They are also bound with ATP-binding region within NBD1 of P-gp, suggesting possible inhibition of ATP hydrolysis. Therefore, guttiferone K and oblongifolin C in Garcinia extracts or fruits have the potential to inhibit P-gp function and might increase the risks of herb–drug interaction when used or consumed with drugs that are P-gp substrates.

Key words: Guttiferone K, Oblongifolin C, P-glycoprotein inhibitor, P-glycoprotein substrate, Nucleotide-binding domain 1.