Abstract |
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-kappaB DNA binding activity in rats, mice, and hepatoma cell lines, and that mice deficient in the p50 subunit of NF-kappaB 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-kappaB 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.
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Authors | Howard P Glauert, Aysegul Eyigor, Job C Tharappel, Simon Cooper, Eun Y Lee, Brett T Spear |
Journal | Toxicological sciences : an official journal of the Society of Toxicology
(Toxicol Sci)
Vol. 90
Issue 2
Pg. 331-6
(Apr 2006)
ISSN: 1096-6080 [Print] United States |
PMID | 16434500
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carcinogens
- NF-kappa B p50 Subunit
- Peroxisome Proliferators
- Pyrimidines
- Diethylnitrosamine
- pirinixic acid
- Acyl-CoA Oxidase
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Topics |
- Acyl-CoA Oxidase
(metabolism)
- Adenoma, Liver Cell
(chemically induced, prevention & control)
- Animals
- Apoptosis
(drug effects)
- Carcinogens
(toxicity)
- Cell Proliferation
(drug effects)
- Diethylnitrosamine
(toxicity)
- Liver
(drug effects, metabolism, pathology)
- Liver Neoplasms, Experimental
(chemically induced, prevention & control)
- Mice
- Mice, Inbred Strains
- Mice, Knockout
- NF-kappa B p50 Subunit
(deficiency, genetics)
- Peroxisome Proliferators
(toxicity)
- Pyrimidines
(toxicity)
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