Elsevier

Toxicology Letters

Volume 204, Issue 1, 4 July 2011, Pages 32-37
Toxicology Letters

Amitriptyline induces coenzyme Q deficiency and oxidative damage in mouse lung and liver

https://doi.org/10.1016/j.toxlet.2011.03.033Get rights and content

Abstract

Amitriptyline is a tricyclic antidepressant commonly prescribed for the treatment of several neuropathic and inflammatory illnesses. We have already reported that amitriptyline has cytotoxic effect in human cell cultures, increasing oxidative stress, and decreasing growth rate and mitochondrial activity. Coenzyme Q (CoQ), a component of the respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In the present work we evaluated lipid peroxidation, a consequence of oxidative stress, and CoQ level in liver, lung, kidney, brain, heart, skeletal muscle, and serum of mice treated with amitriptyline for two weeks. Lipid peroxidation was increased in a dose-dependent manner in all tissues analyzed. CoQ levels were increased in brain, heart, skeletal muscle, and serum, and strongly decreased in liver and lung. The relation between amitriptyline, CoQ, and oxidative stress is discussed.

Highlights

Coenzyme Q (CoQ) has been proposed as a mitochondrial dysfunction marker. ► The antidepressant amitriptyline (Amit) increases oxidative stress, altering mitochondria. ► We show lipid peroxidation in Amit-treated mice and low CoQ level in liver and lung. ► We suggest these organs as the most sensitive to Amit treatment. ► We support the recommendation of CoQ supplementation in patients treated with Amit.

Introduction

Coenzyme Q (CoQ) is a component of the mitochondrial respiratory chain, and is distributed among the cellular membranes. This quinone derivative plays a crucial role in cellular metabolism, acting as the electron carrier between complexes I and II and the complex III of the mitochondrial respiratory chain; regulating uncoupling proteins, the transition pore, β-oxidation of fatty acids, and nucleotide pathway (Turunen et al., 2004). It has been widely demonstrated that CoQ is essential for respiratory chain efficacy (Rauchová et al., 1992). CoQ may leak electrons which in turn may interact with oxygen, resulting in the formation of reactive oxygen species (ROS) (Kowaltowski et al., 2009). All conditions able to alter mitochondria efficiency can enhance ROS production, having a direct and critical effect on oxidative stress. As a consequence of this redox imbalance, peroxidation of lipids may occur, resulting in cell damage. CoQ also acts as a powerful antioxidant which scavenges free radicals, preventing the initiation and propagation of lipid peroxidation in cellular biomembranes (Bentinger et al., 2007). CoQ levels have been suggested to be useful as a mitochondrial dysfunction marker (Haas et al., 2008). Mammalian species with long life span such as humans predominantly exhibit CoQ10, whereas mammalian species such as rats and mice that show relatively short life span primarily contain CoQ9 (Ramasarma, 1985). Nevertheless, both isoforms have the same properties and functions.

Amitriptyline is a frequently prescribed tricyclic antidepressant (TCA) drug that is well known to forensic pathologists, death investigators, and toxicologists; and has long been used for therapeutic treatment of several neuropathic and inflammatory illnesses like fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, and atypical facial pain (Gruber et al., 1996). More recent reports have demonstrated that the toxicity of this drug is due to an increase of oxidative stress, generating high amounts of ROS (Slamon and Pentreath, 2000, Post et al., 2000, Bartholomä et al., 2002). Moreover, when cells were treated with antioxidant agents, the amitriptyline effects decreased (Slamon and Pentreath, 2000). On the other hand, it has been proven that amitriptyline provokes an increase of intracellular lipid peroxidation in mouse 3T3 fibroblasts culture (Viola et al., 2000). Recently, our group has shown that amitriptyline-induced toxicity is caused through mitochondrial dysfunction, and increased mitochondrial ROS production (Cordero et al., 2009). CoQ10 was decreased by amitriptyline treatment, and CoQ10 and alpha-tocopherol supplementation ameliorated amitriptyline-induced toxicity in both cultured human primary fibroblasts and zebrafish embryos (Cordero et al., 2009).

In the present study, in order to elucidate which organ is more affected by amitriptyline toxicity, we have analyzed the levels of both CoQ homologues, CoQ9 and CoQ10, and lipid peroxidation in several tissues and serum of amitriptyline-treated mice.

Section snippets

Animals and treatment

Eighteen C57BL-6 male mice (25–30 g b.w.) were maintained on a 12-h light/dark cycle and were given free access to food and drinking water. Animals were acclimatized for a minimum of 5 days before dosing. All procedures used in these experiments were performed in compliance with the experimentation ethics committee of the University of Seville. Animals were randomly divided into three groups of six animals each: a control group and two treatment groups (10 and 20 mg/kg amitriptyline). Mice

Results

Main organs and serum of mice treated with amitriptyline were analyzed for the study of the toxicological effect of this TCA on CoQ and lipid peroxidation levels. The study was carried out in heart, brain, kidney, skeletal muscle, lung, and liver of three groups of mice: control group (CTL), mice treated with 10 mg/kg amitriptyline (Amit-10) and mice treated with 20 mg/kg amitriptyline (Amit-20). Both CoQ9 (predominant isoform in rodents) and CoQ10 were measured.

Fig. 1 shows the results of CoQ

Discussion

Amitriptyline is a TCA that has been use for decades to treat depression and various types of chronic pain (Watson, 1994). Recently, amitriptyline treatment has being applied for cyclic vomiting syndrome (CVS) (Namin et al., 2007, Boles et al., 2010, Erturk et al., 2010). However, some toxic effects have been attributed to this drug. Several reports showed that the toxicity of this drug is due to the increased oxidative stress by generating high amounts of ROS (Slamon and Pentreath, 2000, Post

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgements

This work has been partially supported by IV Plan Propio de Investigación (University of Seville, ref. 2010/00000453). We thank Itziar Benito for providing the veterinary care of the laboratory animals used in this work.

References (29)

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