Role of the p50 subunit of NF-kappaB in vitamin E-induced changes in mice treated with the peroxisome proliferator, ciprofibrate

• Published in: Food and chemical toxicology 2008-06, Vol.46 (6), p.2062
• Main Authors: Calfee-Mason, Karen G, Lee, Eun Y, Spear, Brett T, Glauert, Howard P
• Format: Article
• Language: English
• Subjects: Acyl-CoA Oxidase - metabolism; Animals; Apoptosis - drug effects; Blotting, Western; Body Weight - drug effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Clofibric Acid - analogs & derivatives; Clofibric Acid - pharmacology; Cyclins - biosynthesis; Diet; DNA - biosynthesis; DNA - genetics; Electrophoretic Mobility Shift Assay; Female; Fibric Acids; Glutathione - metabolism; Liver - enzymology; Liver - metabolism; Mice; NF-kappa B p50 Subunit - physiology; Nuclease Protection Assays; Organ Size - drug effects; Peroxisome Proliferators - pharmacology; RNA - biosynthesis; RNA - genetics; Transcription Factor RelA - metabolism; Vitamin E - pharmacology
• ISSN: 0278-6915
• DOI: 10.1016/j.fct.2008.01.047

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.