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

2.50
Hdl Handle:
http://hdl.handle.net/10146/68619
Title:
Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643.
Authors:
Glauert, Howard P.; Eyigor, Aysegul; Tharappel, Job C.; Cooper, Simon; Lee, Eun Y.; Spear, Brett T.
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.
Citation:
Toxicol. Sci. 2006, 90 (2):331-336
Journal:
Toxicological sciences : an official journal of the Society of Toxicology
Issue Date:
Apr-2006
URI:
http://hdl.handle.net/10146/68619
DOI:
10.1093/toxsci/kfj116
PubMed ID:
16434500
Additional Links:
http://toxsci.oxfordjournals.org/cgi/content/full/90/2/331
Type:
Article
Language:
en
Description:
KEYWORDS - 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.
ISSN:
1096-6080
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorGlauert, Howard P.-
dc.contributor.authorEyigor, Aysegul-
dc.contributor.authorTharappel, Job C.-
dc.contributor.authorCooper, Simon-
dc.contributor.authorLee, Eun Y.-
dc.contributor.authorSpear, Brett T.-
dc.date.accessioned2009-05-20T10:44:39Z-
dc.date.available2009-05-20T10:44:39Z-
dc.date.issued2006-04-
dc.identifier.citationToxicol. Sci. 2006, 90 (2):331-336en
dc.identifier.issn1096-6080-
dc.identifier.pmid16434500-
dc.identifier.doi10.1093/toxsci/kfj116-
dc.identifier.urihttp://hdl.handle.net/10146/68619-
dc.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.en
dc.description.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.en
dc.language.isoenen
dc.relation.urlhttp://toxsci.oxfordjournals.org/cgi/content/full/90/2/331en
dc.subjectNF-Ben
dc.subjectPeroxisomeen
dc.subjectCarcinogenesisen
dc.subjectCell proliferationen
dc.subjectApoptosisen
dc.subject.meshAcyl-CoA Oxidase-
dc.subject.meshAdenoma, Liver Cell-
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshCarcinogens-
dc.subject.meshCell Proliferation-
dc.subject.meshDiethylnitrosamine-
dc.subject.meshLiver-
dc.subject.meshLiver Neoplasms, Experimental-
dc.subject.meshMice-
dc.subject.meshMice, Inbred Strains-
dc.subject.meshMice, Knockout-
dc.subject.meshNF-kappa B p50 Subunit-
dc.subject.meshPeroxisome Proliferators-
dc.subject.meshPyrimidines-
dc.titleInhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643.en
dc.typeArticleen
dc.identifier.journalToxicological sciences : an official journal of the Society of Toxicologyen

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