ToxSci Advance Access published online on January 24, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj116
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1 Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40506; Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40506
* To whom correspondence should be addressed. 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-
Received November 21, 2005
Accepted January 20, 2006
Carcinogenicity
Inhibition of Hepatocarcinogenesis by the Deletion of the p50 Subunit of NF-
Howard P. Glauert 1 *,
Aysegul Eyigor 2,
Job C. Tharappel 1,
Simon Cooper 3,
Eun Y. Lee 4,
and
Brett T. Spear 5
B in Mice Administered the Peroxisome Proliferator Wy-14,643
2 Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506; Uludag University, Faculty of Veterinary Medicine, Department of Food Hygiene and Technology, 16059, Gorukle kampusu, Bursa, Turkey
3 Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506
4 Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506
5 Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40506; Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40506; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506
Howard P. Glauert, E-mail: hglauert{at}uky.edu
Abstract 
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.B; peroxisome; carcinogenesis; cell proliferation; apoptosis.
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