7H-Dibenzo[c,g]carbazole and 5,9-dimethyldibenzo[c,g]carbazole exert multiple toxic events contributing to tumor promotion in rat liver epithelial 'stem-like' cells
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16406433
DOI
10.1016/j.mrfmmm.2005.11.005
PII: S0027-5107(05)00506-3
Knihovny.cz E-resources
- MeSH
- Aryl Hydrocarbon Hydroxylases genetics MeSH
- Cell Death drug effects MeSH
- Cytochrome P-450 CYP1A1 genetics MeSH
- Cytochrome P-450 CYP1A2 genetics MeSH
- Cytochrome P-450 CYP1B1 MeSH
- DNA Primers MeSH
- Epithelial Cells drug effects pathology MeSH
- Liver cytology drug effects MeSH
- Carbazoles toxicity MeSH
- Carcinogens toxicity MeSH
- Rats MeSH
- Methylation MeSH
- Molecular Structure MeSH
- Mutagens MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Rats, Inbred F344 MeSH
- Base Sequence MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 5,9-dimethyldibenzo(c,g)carbazole MeSH Browser
- 7H-dibenzo(c,g)carbazole MeSH Browser
- Aryl Hydrocarbon Hydroxylases MeSH
- Cyp1b1 protein, rat MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1A2 MeSH
- Cytochrome P-450 CYP1B1 MeSH
- DNA Primers MeSH
- Carbazoles MeSH
- Carcinogens MeSH
- Mutagens MeSH
Immature liver progenitor cells have been suggested to be an important target of hepatotoxins and hepatocarcinogens. The goal of the present study was to assess the impact of 7H-dibenzo[c,g]carbazole (DBC) and its tissue-specific carcinogenic N-methyl (N-MeDBC) and 5,9-dimethyl (DiMeDBC) derivatives on rat liver epithelial WB-F344 cells, in vitro model of liver progenitor cells. We investigated the cellular events associated with both tumor initiation and promotion, such as activation of aryl hydrocarbon receptor (AhR), changes in expression of enzymes involved in metabolic activation of DBC and its derivatives, effects on cell cycle, cell proliferation/apoptosis and inhibition of gap junctional intercellular communication (GJIC). N-MeDBC, a tissue-specific sarcomagen, was only a weak inhibitor of GJIC or inducer of AhR-mediated activity, and it did not affect either cell proliferation or apoptosis. DBC was efficient GJIC inhibitor, while DiMeDBC manifested the strongest AhR inducing activity. Accordingly, DiMeDBC was also the most potent inducer of cytochrome P450 1A1 (CYP1A1) and CYP1A2 expression among the three compounds tested. Both DBC and DiMeDBC induced expression of CYP1B1 and aldo-keto reductase 1C9 (AKR1C9). N-MeDBC failed to significantly upregulate CYP1A1/2 and it only moderately increased CYP1B1 or AKR1C9. Only the potent liver carcinogens, DBC and DiMeDBC, caused a significant increase of p53 phosphorylation at Ser15, an increased accumulation of cells in S-phase and apoptosis at micromolar concentrations. In addition, DiMeDBC was found to stimulate cell proliferation of contact-inhibited WB-F344 cells at 1 microM concentration, which is a mode of action that might further contribute to its hepatocarcinogenicity. The present data seem to suggest that the AhR activation, induction of enzymes involved in metabolic activation, inhibition of GJIC or stimulation of cell proliferation might all contribute to the hepatocarcinogenic effects of DBC and DiMeDBC.
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