RBE4 cells are highly resistant to paraquat-induced cytotoxicity: studies on uptake and efflux mechanisms

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

Authors

Vilas Boas, V (Author) Other; Silva, R (Author) Other; Guedes de Pinho, P (Author) FFUP; Carvalho, F (Author) FFUP; Bastos, ML (Author) FFUP; Remiao, F (Author) FFUP

Journal

Title: Journal of Applied Toxicology

Vol. 34 No. 6

Pages: 1023-1030

ISSN: 0260-437X

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 12 Citations

Scopus - 16 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-008-PJK

DOI: 10.1002/jat.2926

Abstract (EN): Paraquat (PQ) is a widely used, highly toxic and non-selective contact herbicide, which has been associated with central neurotoxic effects, namely the development of Parkinson's disease, but whose effects to the blood-brain barrier (BBB) itself have rarely been studied. This work studied the mechanisms of PQ uptake and efflux in a rat's BBB cell model, the RBE4 cells. PQ is believed to enter cells using the basic or neutral amino acid or polyamine transport systems or through the choline-uptake system. In contrast, PQ efflux from cells is reported to bemediated by P-glycoprotein. Therefore, we evaluated PQ-induced cytotoxicity and the effect of some substrates/blockers of these transporters (such as arginine, L-valine, putrescine, hemicholinium-3 and GF120918) on such cytotoxicity. RBE4 cells were shown to be extremely resistant to PQ after 24 h of exposure; even at concentrations as high as 50 mM approximately 45% of the cells remained viable. Prolonging exposure until 48 h elicited significant cytotoxicity only for PQ concentrations above 5 mM. Although hemicholinium-3, a choline-uptake system inhibitor, significantly protected cells against PQ-induced toxicity, none of the effects were observed for arginine, L-valine or putrescine. Meanwhile, inhibiting the efflux pump P-glycoprotein using GF120918 significantly enhanced PQ-induced cytotoxicity. In conclusion, PQ used the choline-uptake system, instead of the transporters for the basic or neutral amino acids or for the polyamines, to enter RBE4 cells. P-glycoprotein extrudes PQ back to the extracellular medium. However, this efflux mechanism only partially explains the observed RBE4 resistance to PQ. Copyright (C) 2013 John Wiley & Sons, Ltd.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8