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Dibenzofuran induces oxidative stress, disruption of trans-mitochondrial membrane potential (ΔΨm) and G1 arrest in human hepatoma cell line.
- Source :
-
Toxicology letters [Toxicol Lett] 2012 Oct 17; Vol. 214 (2), pp. 137-44. Date of Electronic Publication: 2012 Aug 23. - Publication Year :
- 2012
-
Abstract
- Dioxins are a class of extremely toxic environmentally persistent pollutant, comprised of halogenated dibenzo-p-dioxins, dibenzofurans and biphenyls. Despite significant human exposure via multiple routes, very little is known about toxicity induced by dibenzofuran (DF). Current study shed lights on the potential toxicity mechanism of DF using human hepatoma cell line (HepG2). It was observed that the exposure to DF potentiate oxidative stress, apoptosis and necrosis at 10μM within 8h in HepG2 cells. Interestingly, when we pre-incubated the cells with α-NF (1nM) for 12h, an aromatic hydrocarbon receptor antagonist, the IC(50) of DF increased by 14 folds indicating the cytoprotective ability of α-NF from DF induced toxicity. Furthermore, three additional metabolites were observed while studying the metabolic profile of DF in HepG2 cells with and without pre-incubation with α-NF using chromatography-mass spectroscopy (GC-MS). Of these, two metabolites were characterized as dihydroxylated derivative of DF and third metabolite was characterized as quinone derivative of DF. By flow cytometry and confocal laser microscopy analysis we followed the ROS formation after DF (10μM) exposure for 3h. Significantly low ROS was generated in cells which were pre-incubated with α-NF than cells which were not pre-incubated with α-NF underlining the importance of metabolism in DF toxicity. The same pattern of protection was consistent while measuring mitochondrial membrane potential (MMP), i.e., less MMP dip was observed in 'with α-NF pre-incubated and DF (10μM) exposed cells' than 'without α-NF pre-incubated but DF exposed cells'. In cell cycle studies, it was confirmed that cell population of HepG2 at G1 stage progressively increased in number (∼74%) within 24h. Thus, DF and its metabolites induce significantly higher cytotoxicity after metabolism in HepG2 cells than its parent compound (DF) by ROS formation, MMP dip and impaired cell cycle.<br /> (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Apoptosis drug effects
Apoptosis physiology
Benzoflavones pharmacology
Cell Cycle Checkpoints drug effects
Cell Cycle Checkpoints physiology
Cell Survival drug effects
Flow Cytometry
Hep G2 Cells
Humans
Liver metabolism
Liver pathology
Logistic Models
Membrane Potential, Mitochondrial drug effects
Membrane Potential, Mitochondrial physiology
Microscopy, Confocal
Mitochondria, Liver metabolism
Oxidative Stress physiology
Reactive Oxygen Species metabolism
Benzofurans toxicity
Liver drug effects
Mitochondria, Liver drug effects
Oxidative Stress drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3169
- Volume :
- 214
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicology letters
- Publication Type :
- Academic Journal
- Accession number :
- 22944260
- Full Text :
- https://doi.org/10.1016/j.toxlet.2012.08.014