Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity.
Nefazodone (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 μM) 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.
University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Ana Marta
AM
Silva
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Inês A
IA
Barbosa
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Cátia
C
Seabra
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Nuno
N
Beltrão
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Raquel
R
Santos
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Ignacio
I
Vega-Naredo
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal.
Paulo J
PJ
Oliveira
Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park, University of Coimbra, Cantanhede, Portugal. Electronic address: mteroliv@cnc.uc.pt.
Teresa
T
Cunha-Oliveira
D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects*; D010879:Piperazines; D014230:Triazoles / Q000633:toxicity*
D018687:Antidepressive Agents, Second-Generation; D010879:Piperazines; D014230:Triazoles; C051752:nefazodone
Apoptosis; Genotoxicity; Hepatotoxicity; Mitochondria; Nefazodone