Peroxisome Proliferator Induced Transcription Factors

Glauert, Howard

Abstract

Hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rats and mice. Other species, however, including Syrian hamsters, guinea pigs, and primates, have a lower response to peroxisome proliferators. The mechanisms by which these agents act in some species, but not in others, are 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 changes in gene expression in the cell, including the activation of NF-kB in hamsters, a non responsive species. It is therefore hypothesized that the oxidative stress is important in the carcinogenic activity of peroxisome proliferators. The investigator proposes to examine 1) the levels of cellular antioxidants and antioxidant enzymes in rat and hamster liver to determine if differential reductions occur that may explain the activation of NF-kB in rats, but not hamsters, and 2) whether other active oxygen-induced transcription factors are also differentially activated in these two species. These studies will provide information that will address the long-term objective of determining the mechanisms of peroxisome proliferator-induced carcinogenesis.