ToxSci Advance Access originally published online on January 24, 2006
Toxicological Sciences 2006 90(2):331-336; doi:10.1093/toxsci/kfj116
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Inhibition of Hepatocarcinogenesis by the Deletion of the p50 Subunit of NF-
B in Mice Administered the Peroxisome Proliferator Wy-14,643
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* Graduate Center for Nutritional Sciences, Graduate Center for Toxicology, Department of Microbiology, Immunology, and Molecular Genetics, and Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40506; and ¶ Uludag University, Faculty of Veterinary Medicine, Department of Food Hygiene and Technology, 16059, Gorukle kampusu, Bursa, Turkey
Received November 21, 2005; accepted January 20, 2006
Wy-14,643 (WY) is a hypolipidemic drug that induces hepatic peroxisome proliferation and tumors in rodents. We previously showed that peroxisome proliferators increase NF-
B DNA binding activity in rats, mice, and hepatoma cell lines, and that mice deficient in the p50 subunit of NF-B had much lower cell proliferation in response to the peroxisome proliferator ciprofibrate. In this study we examined the promotion of hepatocarcinogenesis by WY in the p50 knockout (–/–) mice. The p50 –/– and wild type mice were first administered diethylnitrosamine (DEN) as an initiating agent. Mice were then fed a control diet or a diet containing 0.05% WY for 38 weeks. Wild-type mice receiving DEN only developed a low incidence of tumors, and the majority of wild-type mice receiving both DEN and WY developed tumors. However, no tumors were seen in any of the p50 –/– mice. Cell proliferation and apoptosis were measured in hepatocytes by BrdU labeling and the TUNEL assay, respectively. Treatment with DEN + WY increased both cell proliferation and apoptosis in both the wild-type and p50 –/– mice; DEN treatment alone has no effect. In the DEN/WY-treated mice, cell proliferation and apoptosis were slightly lower in the p50 –/– mice than in the wild-type mice. These data demonstrate that NF-B is involved in the promotion of hepatic tumors by the peroxisome proliferator WY; however, the difference in tumor incidence could not be attributed to alterations in either cell proliferation or apoptosis.
Key Words: NF-B; peroxisome; carcinogenesis; cell proliferation; apoptosis.
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