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Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643.

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.
AuthorsHoward P Glauert, Aysegul Eyigor, Job C Tharappel, Simon Cooper, Eun Y Lee, Brett T Spear
JournalToxicological 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
PMID16434500 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Carcinogens
  • NF-kappa B p50 Subunit
  • Peroxisome Proliferators
  • Pyrimidines
  • Diethylnitrosamine
  • pirinixic acid
  • Acyl-CoA Oxidase
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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