Oxygenated xanthones as P-glycoprotein modulators at the intestinal barrier: in vitro and docking studies

P-glycoprotein (P-gp) induction and/or activation have been proposed as therapeutic strategies in intoxication scenarios, by reducing the intestinal absorption of xenobiotics, including drugs. Oxygenated xanthones (OXs) have been described as P-gp modulators and, therefore, the main goals of this study were to: (a) investigate the potential modulatory effect of six OXs on P-gp expression and activity in SW480 cells; (b) validate these cells for the screening/identification of P-gp inducers/activators; (c) explore the potential OXs-mediated protective effects against the cytotoxicity of mitoxantrone (MTX), a toxic P-gp substrate. Four OXs (OX2, OX4, OX5, and OX6) increased P-gp expression 24 h after exposure. However, a lack of correlation between P-gp expression and activity was observed for OX1 and OX4. In addition, after a short incubation with the P-gp fluorescent substrate, rhodamine 123, all the studied OXs, except OX3, efficient and immediately increased P-gp activity, suggesting their potential as P-gp activators. Despite these results, OXs failed to afford protection against MTX-induced cytotoxicity. Docking simulations performed in a human P-gp model revealed that the lack of protection may be explained by the different binding locations of OXs and MTX within the P-gp drug-binding pocket. In conclusion, the in vitro results confirmed OXs potential for P-gp induction and/or activation and suggested SW480 cells as a suitable in vitro model for these studies. However, P-gp activation did not protected SW480 cells against MTX cytotoxicity. In silico studies suggested the different binding locations as a limiting step in the P-gp-mediated efflux of its substrates under P-gp activation. [GRAPHICS] .