Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent

Abstract

Sertraline, a selective serotonin reuptake inhibitor, has been used for the treatment of depression. Although it is generally considered safe, cases of sertraline-associated liver injury have been documented; however, the possible mechanism of sertraline-associated hepatotoxicity is entirely unknown. Here, we report that mitochondrial impairment may play an important role in liver injury induced by sertraline. In mitochondria isolated from rat liver, sertraline uncoupled mitochondrial oxidative phosphorylation and inhibited the activities of oxidative phosphorylation complexes I and V. Additionally, sertraline induced Ca(2+)-mediated mitochondrial permeability transition (MPT), and the induction was prevented by bongkrekic acid (BA), a specific MPT inhibitor targeting adenine nucleotide translocator (ANT), implying that the MPT induction is mediated by ANT. In freshly isolated rat primary hepatocytes, sertraline rapidly depleted cellular adenosine triphosphate (ATP) and subsequently induced lactate dehydrogenase leakage; both were attenuated by BA. Our results, including ATP depletion, induction of MPT, inhibition of mitochondrial respiration complexes, and uncoupling oxidative phosphorylation, indicate that sertraline-associated liver toxicity is possibly via mitochondrial dysfunction.

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

“…Although it is generally considered safe, acute liver failure due to sertraline use has been documented [91][92][93][94][95][96][97][98][99]. Sertraline was demonstrated to be toxic in primary rat hepatocytes and human HepG2 cells; mitochondrial dysfunction and apoptosis are the underlying mechanisms [100,101]. Besides mitochondrial dysfunction and apoptosis, ER stress was found to contribute to sertraline's liver toxicity (SC and LG, unpublished data).…”

Comparative effects of fipronil and its metabolites sulfone and desulfinyl on the isolated rat liver mitochondria

“…Experimental evidences indicate that mitochondria represent a critical and preferred target for the action of drugs and toxins. The toxic effects on mitochondria can occur through direct and indirect mechanisms, leading to mitochondrial dysfunction such as changes in electron transport and oxidative phosphorylation, in inner mitochondrial membrane permeability, calcium transport, and the oxidative state as well as a series of other events that deplete ATP (Nadanaciva et al, 2007;Dykens et al, 2008;Castanha-Zanoli et al, 2012;Li et al, 2012).…”

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

“…It has been suggested that the mode of death for acetaminophen's liver toxicity is caspase-independent apoptosis, initiated by activation of PARP-1 [13][14][15]. The widely used antidepressant, sertraline was shown to cause to apoptosis and mitochondrial dysfunction in primary rat hepatocytes and human HepG2 cells [16].…”

“…Moreover, the mechanisms involved in the liver toxicity of anti-diabetic drug troglitazone, include mitochondrial dysfunction, apoptosis, disruption of calcium hemostasis, oxidative stress, and ER stress [23]. Although the most important mechanism for sertaline-induced liver toxicity is mitochondrial dysfunction and apoptosis, ER stress was found to contribute to its liver toxicity [29]. Interestingly, certain antioxidants (butylated hydroxyanisole (BHA), TM2002, and Baicalein) were also shown to cause ER stress in liver [30].…”