Saber UCV
Repositorio Institucional
Repositorio Institucional
Please use this identifier to cite or link to this item:
https://saber.ucv.ve/handle/10872/4637
|
| Title: | Amiodarone Destabilizes Intracellular Ca2+ Homeostasis and Biosynthesis of Sterols in Leishmania mexicana |
| Authors: | Serrano-Martín, Xenón García-Marchan, Yael Fernandez, Alexis Rodríguez, Noris Rojas, Hector Visbal, Gonzalo Benaím, Gustavo |
| Keywords: | Leishmaniasis public health glucantime pentostan toxic effects Trypanosoma cruzi |
| Issue Date: | 2009 |
| Publisher: | ANTIMICROBIAL AGENTS AND CHEMOTHERAPY |
| Citation: | Vol. 53, No. 4, pp. 1403–1410 |
| Abstract: | lucantime and pentostan, which generate toxic effects in treated patients. We have recently shown that amiodarone, frequently used as an antiarrhythmic, possesses activity against Trypanosoma cruzi through the disruption of mitochondrial Ca2 homeostasis and the inhibition of parasite ergosterol biosynthesis, specifically at the level of oxidosqualene cyclase activity (G. Benaim, J. Sanders, Y. Garcia-Marchan, C. Colina, R. Lira, A. Caldera, G. Payares, C. Sanoja, J. Burgos, A. Leon-Rossell, J. Concepcion, A. Schijman, M. Levin, E. Oldfield, and J. Urbina, J. Med. Chem. 49:892–899, 2006). Here we show that at therapeutic concentrations, amiodarone has a profound effect on the viability of Leishmania mexicana promastigotes. Additionally, its effect on the viability of the parasite was greater against intracellular amastigotes than against promastigotes, and it did not affect the host cell. Using fluorimetric and confocal microscopy techniques, we also demonstrated that the mechanism of action of amiodarone was related to the disruption of intracellular Ca2 homeostasis through a direct action not only on the mitochondria but also on the acidocalcisomes. On the other hand, analysis of the free sterols in promastigotes incubated with amiodarone showed that this drug also affected the biosynthesis of 5-dehydroepisterol, which results in squalene accumulation, thus suggesting that amiodarone inhibits the squalene epoxidase activity of the parasite. Taken together, the results obtained in the present work point to a more general effect of amiodarone in trypanosomatids, opening potential therapeutic possibilities for this infectious disease. |
| URI: | http://hdl.handle.net/10872/4637 |
| ISSN: | 0066-4804 doi:10.1128/AAC.01215-08 |
| Appears in Collections: | Artículos Publicados |
Files in This Item:
|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.