Abstract
The capacity of α-mangostin (α-MG) and β-mangostin (β-MG) from mangosteen pericarp on P-glycoprotein (Pgp) in silico, in vitro, and ex vivo was investigated in this study. Screening with the ADMET Predictor™ program predicted the two compounds to be both a Pgp inhibitor and Pgp substrate. The compounds tended to interact with Pgp and inhibit Pgp ATPase activity. Additionally, bidirectional transport on Caco-2 cell monolayers demonstrated a significantly lower efflux ratio than that of the control (α-(44.68) and β-(46.08) MG versus the control (66.26); p < 0.05) indicating an inhibitory effect on Pgp activity. Test compounds additionally revealed a downregulation of MDR1 mRNA expression. Moreover, an ex vivo absorptive transport in everted mouse ileum confirmed the previous results that α-MG had a Pgp affinity inhibitor, leading to an increase in absorption of the Pgp substrate in the serosal side. In conclusion, α- and β-MG have the capability to inhibit Pgp and they also alter Pgp expression, which makes them possible candidates for reducing multidrug resistance. Additionally, they influence the bioavailability and transport of Pgp substrate drugs.
Highlights
Xanthones (α- and β-mangostins) are a significant bioactive compound found in the pericarp of mangosteen (Garcinia mangostana)
The objective of this study is to evaluate the effects of xanthones from mangosteen pericarp on Pgp activities in silico, in vitro, and ex vivo
The structures of the two compounds are xanthone rings with the following functional groups: two double bonds susceptible to hydrogenation, a methoxy group, and hydroxyl groups. The difference between these two compounds is a substitutional group at position 3 of the xanthone ring
Summary
Xanthones (α- and β-mangostins) are a significant bioactive compound found in the pericarp of mangosteen (Garcinia mangostana). Studies have demonstrated that xanthones contain remarkable pharmacological activities [1,2]. Numerous studies focus on the pharmacological and pharmacokinetic activity in vitro, yet there are few in vivo studies, the mechanism on intestinal transporters, P-glycoprotein (Pgp) [1,2,3]. Pgp is an ATP-binding cassette (ABC) transporter abundantly found in many organs together with tumor cells. It is a significant protein in cell membranes which actively pumps many foreign substances out of cells, leading to decreased intracellular xenobiotics concentration. Pgp actively transports out a wide variety of chemically diverse compounds. The substrate to Pgp can lead to failure of chemotherapy in cancer patients whose Pgp was upregulated on the surface of the cancer cells [6]
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