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Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity.

Authors :
Silva AM
Barbosa IA
Seabra C
Beltrão N
Santos R
Vega-Naredo I
Oliveira PJ
Cunha-Oliveira T
Source :
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association [Food Chem Toxicol] 2016 Aug; Vol. 94, pp. 148-58. Date of Electronic Publication: 2016 Jun 08.
Publication Year :
2016

Abstract

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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1873-6351
Volume :
94
Database :
MEDLINE
Journal :
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
Publication Type :
Academic Journal
Accession number :
27288927
Full Text :
https://doi.org/10.1016/j.fct.2016.06.001