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.