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Closed Access item Coenzyme Q10 and alpha-tocopherol protect against amitriptyline toxicity

Authors:Cordero, Mario D.
Moreno-Fernández, Ana M.
Gómez-Skarmeta, José Luis
Miguel, Manuel de
Garrido-Maraver, Juan
Oropesa-Ávila, Manuel
Rodríguez-Hernández, Ángeles
Navas, Plácido
Sánchez-Alcázar, José Antonio
Keywords:Amitriptyline, Human fibroblasts, Coenzyme Q10, Alpha-tocopherol, Oxidative stress, Mitochondrial respiratory chain
Issue Date:20-Jan-2009
Publisher:Elsevier
Citation:Toxicology and Applied Pharmacology 235(3): 329-337 (2009)
Abstract:Since amitriptyline is a very frequently prescribed antidepressant drug, it is not surprising that amitriptyline toxicity is relatively common. Amitriptyline toxic systemic effects include cardiovascular, autonomous nervous, and central nervous systems. To understand the mechanisms of amitriptyline toxicity we studied the cytotoxic effects of amitriptyline treatment on cultured primary human fibroblasts and zebrafish embryos, and the protective role of coenzyme Q10 and alpha-tocopherol, two membrane antioxidants. We found that amitriptyline treatment induced oxidative stress and mitochondrial dysfunction in primary human fibroblasts. Mitochondrial dysfunction in amitriptyline treatment was characterized by reduced expression levels of mitochondrial proteins and coenzyme Q10, decreased NADH:cytochrome c reductase activity, and a drop in mitochondrial membrane potential. Moreover, and as a consequence of these toxic effects, amitriptyline treatment induced a significant increase in apoptotic cell death activating mitochondrial permeability transition. Coenzyme Q10 and alpha-tocopherol supplementation attenuated ROS production, lipid peroxidation, mitochondrial dysfunction, and cell death, suggesting that oxidative stress affecting cell membrane components is involved in amitriptyline cytotoxicity. Furthermore, amitriptyline-dependent toxicity and antioxidant protection were also evaluated in zebrafish embryos, a well established vertebrate model to study developmental toxicity. Amitriptyline significantly increased embryonic cell death and apoptosis rate, and both antioxidants provided a significant protection against amitriptyline embryotoxicity.
Description:9 páginas, 6 figuras. The authors wish to dedicate this manuscript in memoriam to our colleague José A. Mejías Romero.
Publisher version (URL):http://dx.doi.org/10.1016/j.taap.2008.12.026
URI:http://hdl.handle.net/10261/40777
ISSN:0041-008X
E-ISSNmetadata.dc.identifier.doi = DOI:1096-0333
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Appears in Collections:(CABD) Artículos

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