Coenzyme Q10 and alpha-tocopherol protect against amitriptyline toxicity.
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 Q(10) 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 Q(10), 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 Q(10) 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.
Cordero
Mario D
MD
Centro Andaluz de Biología de Desarrollo (CABD), Universidad Pablo de Olavide-CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Sevilla, Spain.
Moreno-Fernández
Ana María
AM
Gomez-Skarmeta
José Luis
JL
de Miguel
Manuel
M
Garrido-Maraver
Juan
J
Oropesa-Avila
Manuel
M
Rodríguez-Hernández
Angeles
A
Navas
Plácido
P
Sánchez-Alcázar
José Antonio
JA
D000639:Amitriptyline / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology; D024502:alpha-Tocopherol / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D014451:Ubiquinone; D000639:Amitriptyline; C024989:coenzyme Q10; D024502:alpha-Tocopherol