Abstract
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.
Highlights
P-glycoprotein (P-gp) is the best characterized efflux protein pump of the adenosine triphosphate (ATP) binding cassette (ABC) superfamily of transporters, belonging to the ABC subfamily B (ABCB) [1,2,3]
It is believed that this 170 kDa protein is a result of a gene duplication event, where two transmembrane domains (TMDs), which usually contain six transmembrane α-helices (TMHs) and one nucleotide binding domain (NBD) each, are fused together [1,7]
Silva et al, using Caco-2 cells as an in vitro model, further demonstrated a concentration-dependent increase in P-gp expression induced by colchicine, a known P-gp substrate and inducer (129%, 135%, 145%, 150%, 154%, and 183% after 24 h of exposure to 0.5, 1, 5, 10, 50, and 100 μM colchicine, correspondingly, when compared to control cells (100%)) with no significant changes in the protein transport activity. These results suggest that P-gp incorporation into the cell membrane does not guarantee protein functionality, with the lack of an effect of colchicine on P-gp activity explained by its potential action as a P-gp competitive inhibitor, as supported by the performed in silico studies [26]
Summary
P-glycoprotein (P-gp) is the best characterized efflux protein pump of the adenosine triphosphate (ATP) binding cassette (ABC) superfamily of transporters, belonging to the ABC subfamily B (ABCB) [1,2,3]. Ling in 1976 [4] It is a well-studied protein due to its importance in the protection of sensitive tissues against toxic xenobiotics, this mechanism it is not yet fully understood, and to its important role in the multi-drug-resistance (MDR) phenomenon in cancer chemotherapy [1,4,5]. P-gp is encoded by two multidrug resistance (MDR) genes, MDR1/ABCB1, coding to the drug transporter associated with the MDR phenotype, and MDR3/ABCB4 (or MDR2), coding to a protein that functions as a phosphatidylcholine translocase, exporting this phospholipid into the bile [6]. It is believed that this 170 kDa protein is a result of a gene duplication event, where two transmembrane domains (TMDs), which usually contain six transmembrane α-helices (TMHs) and one nucleotide binding domain (NBD) each, are fused together [1,7]. NBD regions, located in the cytoplasmic membrane side, bind and hydrolase ATP producing energy to execute the membrane passage, with the TMHs responsible for the pathway of this passage [3,7]
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