Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643.
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AbstractWy-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.
CitationToxicol. Sci. 2006, 90 (2):331-336
DescriptionKEYWORDS - CLASSIFICATION: Acyl-CoA Oxidase;Adenoma,Liver Cell;Animals;Apoptosis;chemically induced;Carcinogens;Cell Proliferation;deficiency;drug effects;Diethylnitrosamine;genetics;Liver;Liver Neoplasms,Experimental;metabolism;mechanisms of carcinogenesis;Mice;Mice,Inbred Strains;Mice,Knockout;NF-kappa B;NF-kappa B p50 Subunit;pathology;prevention & control;Peroxisome Proliferators;Pyrimidines;Research;toxicity.
- Cell proliferation and apoptosis are altered in mice deficient in the NF-kappaB p50 subunit after treatment with the peroxisome proliferator ciprofibrate.
- Authors: Tharappel JC, Nalca A, Owens AB, Ghabrial L, Konz EC, Glauert HP, Spear BT
- Issue date: 2003 Oct
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- Authors: Woods CG, Burns AM, Bradford BU, Ross PK, Kosyk O, Swenberg JA, Cunningham ML, Rusyn I
- Issue date: 2007 Aug
- Oxidants from nicotinamide adenine dinucleotide phosphate oxidase are involved in triggering cell proliferation in the liver due to peroxisome proliferators.
- Authors: Rusyn I, Yamashina S, Segal BH, Schoonhoven R, Holland SM, Cattley RC, Swenberg JA, Thurman RG
- Issue date: 2000 Sep 1
- Differences between the promoting activities of the peroxisome proliferator WY-14,643 and phenobarbital in rat liver.
- Authors: Cattley RC, Popp JA
- Issue date: 1989 Jun 15
- Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation.
- Authors: Kiss A, Ortiz-Aguayo R, Sharp R, Merlino G, Thorgeirsson SS, Gonzalez FJ, Peters JM
- Issue date: 2001 Jun