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Chem Biol Interact ; 207: 41-51, 2014 Jan 25.
Article in English | MEDLINE | ID: mdl-24246761

ABSTRACT

Plasma membrane is an early target of polycyclic aromatic hydrocarbons (PAH). We previously showed that the PAH prototype, benzo[a]pyrene (B[a]P), triggers apoptosis via DNA damage-induced p53 activation (genotoxic pathway) and via remodeling of the membrane cholesterol-rich microdomains called lipid rafts, leading to changes in pH homeostasis (non-genotoxic pathway). As omega-3 (n-3) fatty acids can affect membrane composition and function or hamper in vivo PAH genotoxicity, we hypothesized that addition of physiologically relevant levels of polyunsaturated n-3 fatty acids (PUFAs) might interfere with B[a]P-induced toxicity. The effects of two major PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were tested on B[a]P cytotoxicity in the liver epithelial cell line F258. Both PUFAs reduced B[a]P-induced apoptosis. Surprisingly, pre-treatment with DHA increased the formation of reactive B[a]P metabolites, resulting in higher levels of B[a]P-DNA adducts. EPA had no apparent effect on B[a]P metabolism or related DNA damage. EPA and DHA prevented B[a]P-induced apoptotic alkalinization by affecting Na(+)/H(+) exchanger 1 activity. Thus, the inhibitory effects of omega-3 fatty acids on B[a]P-induced apoptosis involve a non-genotoxic pathway associated with plasma membrane remodeling. Our results suggest that dietary omega-3 fatty acids may have marked effects on the biological consequences of PAH exposure.


Subject(s)
Apoptosis/drug effects , Cell Membrane/metabolism , Fatty Acids, Omega-3/pharmacology , Protective Agents/pharmacology , Signal Transduction/drug effects , Sodium-Hydrogen Exchangers/metabolism , Animals , Benzo(a)pyrene , Cell Line , Cell Membrane/drug effects , Cholesterol/metabolism , Cytochrome P-450 Enzyme System/metabolism , DNA Damage , Docosahexaenoic Acids/pharmacology , Eicosapentaenoic Acid/pharmacology , Hydrogen-Ion Concentration/drug effects , Intracellular Space/drug effects , Intracellular Space/metabolism , Lipids/chemistry , Membrane Microdomains/drug effects , Membrane Microdomains/metabolism , Models, Biological , Protein Transport/drug effects , Rats , Sodium-Hydrogen Exchanger 1 , Tumor Suppressor Protein p53/metabolism
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