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Cooperative interaction of benzo[a]pyrene and ethanol on plasma membrane remodeling is responsible for enhanced oxidative stress and cell death in primary rat hepatocytes.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2014 Jul; Vol. 72, pp. 11-22. Date of Electronic Publication: 2014 Mar 26. - Publication Year :
- 2014
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Abstract
- Several epidemiologic studies have shown an interactive effect of heavy smoking and heavy alcohol drinking on the development of hepatocellular carcinoma. It has also been recently described that chronic hepatocyte death can trigger excessive compensatory proliferation resulting later in the formation of tumors in mouse liver. As we previously demonstrated that both benzo[a]pyrene (B[a]P), an environmental agent found in cigarette smoke, and ethanol possess similar targets, especially oxidative stress, to trigger death of liver cells, we decided to study here the cellular and molecular mechanisms of the effects of B[a]P/ethanol coexposure on cell death. After an 18-h incubation with 100nM B[a]P, primary rat hepatocytes were supplemented with 50mM ethanol for 5 or 8h. B[a]P/ethanol coexposure led to a greater apoptotic cell death that could be linked to an increase in lipid peroxidation. Plasma membrane remodeling, as depicted by membrane fluidity elevation and physicochemical alterations in lipid rafts, appeared to play a key role, because both toxicants acted with specific complementary effects. Membrane remodeling was shown to induce an accumulation of lysosomes leading to an important increase in low-molecular-weight iron cellular content. Finally, ethanol metabolism, but not that of B[a]P, by providing reactive oxygen species, induced the ultimate toxic process. Indeed, in lysosomes, ethanol promoted the Fenton reaction, lipid peroxidation, and membrane permeabilization, thereby triggering cell death. To conclude, B[a]P exposure, by depleting hepatocyte membrane cholesterol content, would constitute a favorable ground for a later toxic insult such as ethanol intoxication. Membrane stabilization of both plasma membrane and lysosomes might be a potential target for further investigation considering cytoprotective strategies.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis drug effects
Carcinogens toxicity
Central Nervous System Depressants toxicity
Hepatocytes pathology
Lipid Peroxidation drug effects
Lysosomes drug effects
Microscopy, Electron, Transmission
Rats
Rats, Sprague-Dawley
Benzo(a)pyrene toxicity
Cell Membrane drug effects
Ethanol toxicity
Hepatocytes drug effects
Oxidative Stress drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 72
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 24681337
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2014.03.029