Several diverse chemicals, including phenobarbital, peroxisome proliferators, and TCDD, have tumor promoting activity in the liver. The mechanisms by which these agents act is unclear, but may be related to the induction of cell proliferation, the inhibition of apoptosis, or the production of active oxygen. The production of active oxygen could lead to several deleterious changes in the cell, including lipid peroxidation, oxidative DNA damage, or changes in gene expression. The transcription factor NF-kappaB is activated by active oxygen and, after binding to DNA, brings about changes in gene expression which may lead to cell proliferation and an inhibition in apoptosis. Both phenobarbital and the peroxisome proliferator ciprofibrate have been found to activate NF- kappaB; the mechanism by which ciprofibrate activates NF-kappaB in vitro has been found to be mediated by active oxygen. It is therefore hypothesized that activation of NF-kappaB by peroxisome proliferators (and other tumor promoters such as phenobarbital) contributes to their carcinogenic and promoting activities. We will examine 1) if peroxisome proliferators and phenobarbital activate NF-kappaB through active oxygen intermediates; 2) the effect of NF-kappa activation on the expression of other genes that are likely to be related to tumor promotion; 3) whether NF-kappaB activation is occurring in Kupffer cells in addition to hepatocytes, and if so, whether the activation is mediated by active oxygen, resulting in NF-kappaB activation of gene expression; and 4) whether overexpressing dominant negative forms of NF-kappaB in transgenic animals inhibits peroxisome proliferator- and phenobarbital-induced NF- kappaB activation, cell proliferation,and tumor promotion. These studies will show if NF-kappaB activation is necessary for the hepatic promoting activities of peroxisome proliferators and other chemicals, and will elucidate the mechanism by which NF-kappaB activation influences hepatic tumor promotion.
