title: Role of the p50 subunit of NF-kappaB in vitamin E-induced changes in mice treated with the peroxisome proliferator, ciprofibrate.
abstract: Peroxisome proliferators (PPs) are a diverse class of chemicals, which cause a dramatic increase in the size and number of hepatic peroxisomes in rodents and eventually lead to the development of hepatic tumors. Nuclear factor-kappaB (NF-kappaB) is a transcription factor activated by reactive oxygen and is involved in cell proliferation and apoptosis. Previously we found that the peroxisome proliferator ciprofibrate (CIP) activates NF-kappaB and that dietary vitamin E decreases CIP-induced NF-kappaB DNA binding. We, therefore, hypothesized that inhibition of NF-kappaB by vitamin E is necessary for effects of vitamin E on CIP-induced cell proliferation and the inhibition of apoptosis by CIP. Sixteen B6129 female mice (p50+/+) and twenty mice deficient in the p50 subunit of NF-kappaB (p50-/-) were fed a purified diet containing 10 or 250mg/kg vitamin E (alpha-tocopherol acetate) for 28 days. At that time, half of the mice were placed on the same diet with 0.01% CIP for 10 days. CIP treatment increased the DNA binding activity of NF-kappaB and cell proliferation, but had no significant effect on apoptosis. Compared to wild-type mice, the p50-/- mice had lower NF-kappaB activation, higher basal levels of cell proliferation and apoptosis, and a lower ratio of reduced glutathione to oxidized glutathione (GSH/GSSG). There was approximately a 60% reduction in cell proliferation in the CIP-treated p50-/- mice fed higher vitamin E in comparison to the p50-/- mice fed lower vitamin E. Dietary vitamin E also inhibited the DNA binding activity of NF-kappaB, increased apoptosis, and increased the GSH/GSSG ratio. This study shows the effects of vitamin E on cell growth parameters do not appear to be solely through decreased NF-kappaB activation, suggesting that vitamin E is acting by other molecular mechanisms.
authors.affiliation: Graduate Center for Nutritional Sciences, University of Kentucky, 222 Funkhouser Building, Lexington, KY 40506-0054, USA.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Calfee-Mason
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Brett T
authors.initials: BT
authors.lastname: Spear
authors.forename: Howard P
authors.initials: HP
authors.lastname: Glauert
mesh_terms: D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004032:Diet; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D058607:Fibric Acids; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D023282:Nuclease Protection Assays; D009929:Organ Size / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D016213:Cyclins; D058607:Fibric Acids; D052002:NF-kappa B p50 Subunit; D020025:Peroxisome Proliferators; D051996:Transcription Factor RelA; D014810:Vitamin E; D002995:Clofibric Acid; D012313:RNA; D004247:DNA; D042962:Acyl-CoA Oxidase; C019304:ciprofibrate; D005978:Glutathione