Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity

Abstract

a b s t r a c tNefazodone (NEF) is an antidepressive agent that was widely used in the treatment of depression until its withdrawal from the market, due to reports of liver injury and failure. NEF hepatotoxicity has been associated with mitochondrial impairment due to interference with the OXPHOS enzymatic activities, increased ROS generation and decreased antioxidant defenses. However, the mechanisms by which NEF induces mitochondrial dysfunction in hepatocytes are not completely understood. Here, we investigated the mitochondrial mechanisms affected upon NEF exposure and whether these might be linked to drug hepatotoxicity, in order to infer liabilities of future drug candidates.Two moderately hepatotoxic NEF concentrations (20 and 50 mM) were selected from dose-response growth curves performed in HepG2 cells. Cell viability, caspase activity, nuclear morphology, mitochondrial transmembrane potential, mitochondrial superoxide levels, and the expression of genes associated with different cellular pathways were evaluated at different time points.NEF treatment led to an increase in the expression of genes associated with DNA-damage response, antioxidant defense and apoptosis and a decreased expression of genes encoding proteins involved in oxidative phosphorylation, DNA repair, cell proliferation and cell cycle progression, which seem to constitute mechanisms underlying the observed mitochondrial and cell function impairment.

Identifying multiscale translational safety biomarkers using a network-based systems approach

“…We further selected in the screening compounds belonging to the category “Positive compounds for scNecrosis4” when showing a strong positive correlation between module’s TG:rLIV:176 EGs and single cell necrosis score (Pearson R > 0.5, Figures S11 A and S11B, a total of 12 compounds). In the group “No data in TG” we included three compounds because of known molecular mechanisms that could trigger the Atf4 response or DILI annotations: nefazodone, Most-DILI-Concern according to DILI ranking 25 and ER stress and mitochondrial dysfunction inducer, 48 , 49 , 50 thapsigargin, ER stress inducer 21 and tert-butylhydroquinone, Nrf2 activator. 51 To select compounds for the group “Negative for scNecrosis no path”, we focused on compounds having Less-DILI-Concerns in the FDA DILI ranking.…”

Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes

“…*p < 0.05 compared to control. seemed to increase perinuclear mitochondrial polarization, which can be an early feature of apoptosis (Sanchez-Alcazar et al, 2000;Giovannini et al, 2002;Iijima et al, 2003;Liu et al, 2005;Cao et al, 2007;Silva et al, 2016). Electrophysiologically, DOX has previously been reported to affect beat period, spike amplitude and corrected field potential duration in a time and dose-dependent manner (Abassi et al, 2012;Koci et al, 2017).…”

Investigation of genotoxicity, mutagenicity, and cytotoxicity in erythrocytes of Nile tilapia (Oreochromis niloticus) after fluoxetine exposure

“…The nitro groups might be transformed into nitroso compounds and form alkylating molecules, leading to lesions such as DNA adducts, DNA strand breaks and DNA cross-links [59] . In terms of indirect mechanisms, antidepressants might influence organelles, such as mitochondria [20] . It is mainly associated with oxidative stress caused by reactive oxygen species (ROS), leading to DNA damage, such as base modification and single- and double-strand breaks [61] , as well as alterations in the expression of genes associated with the DNA damage response, DNA repair, cell proliferation and cell cycle control [20] .…”

“…In terms of indirect mechanisms, antidepressants might influence organelles, such as mitochondria [20] . It is mainly associated with oxidative stress caused by reactive oxygen species (ROS), leading to DNA damage, such as base modification and single- and double-strand breaks [61] , as well as alterations in the expression of genes associated with the DNA damage response, DNA repair, cell proliferation and cell cycle control [20] . For example, intracellular ROS production in haemocytes of Mytilus edulis was increased after exposure to FLX at concentrations of 10 and 50 mg/L, thus affecting haemocyte DNA damage [62] .…”

“…To assess the impact of waterborne contaminants, fish are considered a good choice for use in biomonitoring because they are susceptible to environmental changes [18] , [19] . Currently, the ability of fish is not only used for the assessment of the impacts of water contaminants but can also be used as a biological indicator for the investigation of genotoxic, mutagenic, and carcinogenic effects in aquatic organisms, as well as to prevent these effects from entering the food chain [20] . Nile tilapia ( Oreochromis niloticus ) is one of the fish commonly used in toxicity testing because of its ability to adapt and tolerate environmental pollution very well [21] .…”