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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.
AuthorsKaren G Calfee-Mason, Eun Y Lee, Brett T Spear, Howard P Glauert
JournalFood and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 46 Issue 6 Pg. 2062-73 (Jun 2008) ISSN: 0278-6915 [Print] England
PMID18336980 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cyclins
  • Fibric Acids
  • NF-kappa B p50 Subunit
  • Peroxisome Proliferators
  • Transcription Factor RelA
  • Vitamin E
  • Clofibric Acid
  • RNA
  • DNA
  • Acyl-CoA Oxidase
  • ciprofibrate
  • Glutathione
Topics
  • Acyl-CoA Oxidase (metabolism)
  • Animals
  • Apoptosis (drug effects)
  • Blotting, Western
  • Body Weight (drug effects)
  • Cell Nucleus (drug effects, metabolism)
  • Clofibric Acid (analogs & derivatives, pharmacology)
  • Cyclins (biosynthesis)
  • DNA (biosynthesis, genetics)
  • Diet
  • Electrophoretic Mobility Shift Assay
  • Female
  • Fibric Acids
  • Glutathione (metabolism)
  • Liver (enzymology, metabolism)
  • Mice
  • NF-kappa B p50 Subunit (physiology)
  • Nuclease Protection Assays
  • Organ Size (drug effects)
  • Peroxisome Proliferators (pharmacology)
  • RNA (biosynthesis, genetics)
  • Transcription Factor RelA (metabolism)
  • Vitamin E (pharmacology)

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