Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: <i>In Vitro</i>, <i>Ex Vivo</i>, and <i>In Silico</i> Studies

• Main Authors: Eva Martins, Vera Silva, Agostinho Lemos, Andreia Palmeira, Ploenthip Puthongking, Emília Sousa, Carolina Rocha-Pereira, Carolina I. Ghanem, Helena Carmo, Fernando Remião, Renata Silva
• Format: Article
• Language: English
• Published: MDPI AG 2019-02-01
• Series: Molecules
• Subjects: P-glycoprotein; induction; activation; oxygenated xanthones; intestinal barrier; intoxication scenarios
• Online Access: https://www.mdpi.com/1420-3049/24/4/707

P-glycoprotein (P-gp) plays a crucial role in the protection of susceptible organs, by significantly decreasing the absorption/distribution of harmful xenobiotics and, consequently, their toxicity. Therefore, P-gp has been proposed as a potential antidotal pathway, when activated and/or induced. Knowing that xanthones are known to interact with P-gp, the main goal was to study P-gp induction or/and activation by six new oxygenated xanthones (OX 1-6). Furthermore, the potential protection of Caco-2 cells against paraquat cytotoxicity was also assessed. The most promising compound was further tested for its ability to increase P-gp activity <i>ex vivo</i>, using everted intestinal sacs from adult Wistar-Han rats. The oxygenated xanthones interacted with P-gp <i>in vitro</i>, increasing P-gp expression and/or activity 24 h after exposure. Additionally, after a short-incubation period, several xanthones were identified as P-gp activators, as they immediately increased P-gp activity. Moreover, some xanthones decreased PQ cytotoxicity towards Caco-2 cells, an effect prevented under P-gp inhibition. <i>Ex vivo</i>, a significant increase in P-gp activity was observed in the presence of OX6, which was selectively blocked by a model P-gp inhibitor, zosuquidar, confirming the <i>in vitro</i> results. Docking simulations between a validated P-gp model and the tested xanthones predicted these interactions, and these compounds also fitted onto previously described P-gp induction and activation pharmacophores. In conclusion, the <i>in vitro</i>, <i>ex vivo</i>, and <i>in silico</i> results suggest the potential of some of the oxygenated xanthones in the modulation of P-gp, disclosing new perspectives in the therapeutics of intoxications by P-gp substrates.