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Open AccessFeature PaperArticle

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

1
UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
2
Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
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Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
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Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal
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Universidad de Buenos Aires, CONICET, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA), Buenos Aires C1053, Argentina
*
Authors to whom correspondence should be addressed.
Academic Editors: Maria Emília De Sousa, Honorina Cidade and Carlos Manuel Afonso
Molecules 2019, 24(4), 707; https://doi.org/10.3390/molecules24040707
Received: 7 January 2019 / Revised: 1 February 2019 / Accepted: 9 February 2019 / Published: 15 February 2019
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 ex vivo, using everted intestinal sacs from adult Wistar-Han rats. The oxygenated xanthones interacted with P-gp in vitro, 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. Ex vivo, 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 in vitro 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 in vitro, ex vivo, and in silico 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. View Full-Text
Keywords: P-glycoprotein; induction; activation; oxygenated xanthones; intestinal barrier; intoxication scenarios P-glycoprotein; induction; activation; oxygenated xanthones; intestinal barrier; intoxication scenarios
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MDPI and ACS Style

Martins, E.; Silva, V.; Lemos, A.; Palmeira, A.; Puthongking, P.; Sousa, E.; Rocha-Pereira, C.; Ghanem, C.I.; Carmo, H.; Remião, F.; Silva, R. Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies. Molecules 2019, 24, 707. https://doi.org/10.3390/molecules24040707

AMA Style

Martins E, Silva V, Lemos A, Palmeira A, Puthongking P, Sousa E, Rocha-Pereira C, Ghanem CI, Carmo H, Remião F, Silva R. Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies. Molecules. 2019; 24(4):707. https://doi.org/10.3390/molecules24040707

Chicago/Turabian Style

Martins, Eva; Silva, Vera; Lemos, Agostinho; Palmeira, Andreia; Puthongking, Ploenthip; Sousa, Emília; Rocha-Pereira, Carolina; Ghanem, Carolina I.; Carmo, Helena; Remião, Fernando; Silva, Renata. 2019. "Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies" Molecules 24, no. 4: 707. https://doi.org/10.3390/molecules24040707

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