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Antioxidant protection against PCB-mediated endothelial cell activation
Journal article   Open access   Peer reviewed

Antioxidant protection against PCB-mediated endothelial cell activation

R Slim, M Toborek, L W Robertson and B Hennig
Toxicological sciences, Vol.52(2), pp.232-239
12/1999
DOI: 10.1093/toxsci/52.2.232
PMID: 10630576
url
https://doi.org/10.1093/toxsci/52.2.232View
Published (Version of record) Open Access

Abstract

Certain environmental contaminants such as polyhalogenated aromatic hydrocarbons may be implicated in diseases of the vasculature by compromising normal functions of vascular endothelial cells. We have shown previously that 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an aryl hydrocarbon (Ah) receptor agonist, can cause disruption of endothelial barrier function. This was supported by an increase in oxidative stress as measured by enhanced 2',7'-dichlorofluorescein (DCF) fluorescence and activation of the oxidative stress-sensitive transcription factor NF-kappaB. We have now tested the protective effects of antioxidants vitamin E (alpha-tocopherol) and pyrrolidine dithiocarbamate (PDTC) on endothelial cell activation induced by PCB 77. Only vitamin E completely blocked PCB 77-mediated endothelial barrier dysfunction. This protective effect by vitamin E was associated with a decrease in both oxidative stress, as measured by DCF fluorescence, as well as in NF-kappaB activation. Furthermore, vitamin E decreased PCB 77-mediated production of the inflammatory cytokine IL-6. Although pretreatment of endothelial cells with PDTC prevented the induction of NF-kappaB by PCB 77, this inhibition was not associated with a decrease in DCF levels or protection against endothelial barrier dysfunction. Pretreatment with alpha-naphthoflavone (alpha-NF), an Ah receptor partial antagonist and specific inhibitor of cytochrome P450 1A, partially protected against PCB 77-induced endothelial barrier dysfunction. This observation was paralleled by the fact that alpha-NF did not fully antagonize the PCB-induced increase in DCF in endothelial cells. Furthermore, PCB-mediated induction of NF-kappaB and production of IL-6 were only partially blocked by alpha-NF. Of all the tested compounds (vitamin E, PDTC and alpha-NF), vitamin E was most potent in blocking PCB 77-mediated endothelial cell activation. These data give an insight into the potential use of vitamin E and related antioxidants to limit PCB-mediated cell injury and into the use of alpha-NF to explore mechanisms underlying the injurious potential of Ah receptor agonists.
 Electrophoresis Endothelium, Vascular - cytology NF-kappa B - antagonists & inhibitors Albumins - metabolism Cytosol - drug effects NF-kappa B - metabolism Polychlorinated Biphenyls - antagonists & inhibitors Antioxidants - pharmacology Carcinogens - toxicity Pyrrolidines - pharmacology Animals Cell Nucleus - metabolism Thiocarbamates - pharmacology Benzoflavones - pharmacology Carcinogens - antagonists & inhibitors Polychlorinated Biphenyls - toxicity Swine Carcinogens - chemical synthesis Interleukin-6 - biosynthesis Polychlorinated Biphenyls - chemical synthesis Cytosol - metabolism Oxidative Stress - drug effects Cell Nucleus - drug effects Vitamin E - pharmacology

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