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Transgenic disruption of gap junctional intercellular communication enhances early but not late stage hepatocarcinogenesis in the rat.
- Source :
-
Toxicologic pathology [Toxicol Pathol] 2005; Vol. 33 (6), pp. 695-701. - Publication Year :
- 2005
-
Abstract
- Much experimental evidence supports the conclusion that loss of gap junctional intercellular communication (GJIC) contributes to carcinogenesis. Transgenic rats featuring a dominant negative mutant of the connexin 32 gene under albumin promoter control (Cx32Delta Tg-High and Cx32Delta Tg-Low lines, respectively with high and low copy numbers of the transgene) have disrupted GJIC, as demonstrated by scrape dye-transfer assay in vivo as previous report by Asamoto et al. (2004). In the present study, we investigated the susceptibility of these transgenic rats to a single intraperitoneal administration of diethylnitrosamine (DEN), and found a significant increase in preneoplastic glutathione S-transferase placental form (GST-P) positive lesions in the livers of Cx32Delta Tg-High but not Cx32Delta Tg-Low rats. However, incidences of adenomas and hepatocellular carcinomas were not elevated at the end of the experiment (52 weeks). In addition, we investigated the promotional effect of phenobarbital (PB) on Cx32Delta Tg-High rats pretreated with DEN and found enhanced formation of GST-P positive lesions, in contrast to the lack of promoting effects reported for Cx32 deficient mice. The results indicate that although both high and low expression of the dominant negative connexin 32 mutant gene in our rats is able to inhibit gap junctional capacity, only high expression is effective at enhancing susceptibility to early stage DEN-induced liver carcinogenesis.
- Subjects :
- Alkylating Agents
Animals
Animals, Genetically Modified
Cell Communication drug effects
Cocarcinogenesis
Connexins analysis
Connexins genetics
Connexins metabolism
Diethylnitrosamine
Disease Susceptibility
Enzyme Induction
Gap Junctions drug effects
Gap Junctions metabolism
Hepatectomy
Liver Neoplasms, Experimental chemically induced
Liver Neoplasms, Experimental enzymology
Liver Regeneration physiology
Male
Mutation
Phenobarbital administration & dosage
Phenobarbital pharmacology
Precancerous Conditions chemically induced
Precancerous Conditions enzymology
Rats
Time Factors
Gap Junction beta-1 Protein
Cell Communication genetics
Gap Junctions genetics
Glutathione Transferase biosynthesis
Liver Neoplasms, Experimental genetics
Precancerous Conditions genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0192-6233
- Volume :
- 33
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Toxicologic pathology
- Publication Type :
- Academic Journal
- Accession number :
- 16243774
- Full Text :
- https://doi.org/10.1080/01926230500330313