title: Antioxidant protection against PCB-mediated endothelial cell activation.
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.
authors.affiliation: Department of Nutrition and Food Science, Graduate Center for Toxicology, University of Kentucky, Lexington 40506-0054, USA.
authors.forename: R
authors.initials: R
authors.lastname: Slim
authors.forename: M
authors.initials: M
authors.lastname: Toborek
authors.forename: L W
authors.initials: LW
authors.lastname: Robertson
authors.forename: B
authors.initials: B
authors.lastname: Hennig
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004586:Electrophoresis; D004730:Endothelium, Vascular / Q000166:cytology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000633:toxicity*; D011759:Pyrrolidines / Q000494:pharmacology; D013552:Swine; D013859:Thiocarbamates / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000418:Albumins; D000975:Antioxidants; D001571:Benzoflavones; D002273:Carcinogens; D015850:Interleukin-6; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014810:Vitamin E; C020972:pyrrolidine dithiocarbamic acid; C011512:alpha-naphthoflavone; D011078:Polychlorinated Biphenyls