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

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-κB (NF-κB) 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-κB and that dietary vitamin E decreases CIP-induced NF-κB DNA binding. We, therefore, hypothesized that inhibition of NF-κB 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-κB (p50−/−) were fed a purified diet containing 10 or 250 mg/kg vitamin E (α-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-κB and cell proliferation, but had no significant effect on apoptosis. Compared to wild-type mice, the p50−/− mice had lower NF-κB 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-κB, 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-κB activation, suggesting that vitamin E is acting by other molecular mechanisms.