Induction and activation of P-glycoprotein by dihydroxylated xanthones protect against the cytotoxicity of the P-glycoprotein substrate paraquat

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Renata Silva (Author) Other; Emilia Sousa (Author) Other; Helena Carmo (Author) FFUP; Andreia Palmeira (Author) Other; Daniel Jose Barbosa (Author) Other; Mariline Gameiro (Author) Other; Madalena Pinto (Author) FFUP; Maria de Lourdes Bastos (Author) FFUP; Fernando Remiao (Author) FFUP

Journal

Title: Archives of Toxicology

Vol. 88

Pages: 937-951

ISSN: 0340-5761

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 33 Citations

ISI Web of Science

Scopus - 32 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Basic medicine

CORDIS: Health sciences > Pharmacological sciences > Toicology

Other information

Authenticus ID: P-009-C2D

DOI: 10.1007/s00204-014-1193-y

Abstract (EN): Xanthones are a family of compounds with several known biological activities and therapeutic potential for which information on their interaction with membrane transporters is lacking. Knowing that P-glycoprotein (P-gp) acts as a cellular defense mechanism by effluxing its toxic substrates, the aim of this study was to investigate the potential of five dihydroxylated xanthones as inducers of P-gp expression and/or activity and to evaluate whether they could protect Caco-2 cells against the cytotoxicity induced by the toxic P-gp substrate paraquat (PQ). After 24 h of incubation, all tested xanthones caused a significant increase in both P-gp expression and activity, as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, after a short 45-min incubation, all the tested xanthones induced a rapid increase in P-gp activity, indicating direct pump activation without increased P-gp protein expression. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, demonstrating to be P-gp substrates. Moreover, when simultaneously incubated with PQ, all xanthones significantly reduced the cytotoxicity of the herbicide, and these protective effects were completely reversed upon incubation with a specific P-gp inhibitor. In silico studies evaluating the interactions between xanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. A quantitative structure-activity relationship model was developed and validated, and the maximal partial charge for an oxygen atom was the descriptor predicted as being implicated in P-gp activation by the dihydroxylated xanthones. These results disclose new perspectives in preventing PQ- and other P-gp substrates-induced poisonings.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15