Toxicological Sciences, Vol 52, 232-239, Copyright © 1999 by Society of Toxicology
R Slim, M Toborek, LW Robertson and B Hennig
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.
ARTICLES
Antioxidant protection against PCB-mediated endothelial cell activation
Department of Nutrition and Food Science, Graduate Center for Toxicology, University of Kentucky, Lexington 40506-0054, USA.
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