7H-dibenzo(c,g)carbazole OR C013478 Dotaz Zobrazit nápovědu
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.
- MeSH
- aromatické hydroxylasy genetika MeSH
- buněčná smrt účinky léků MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- cytochrom P-450 CYP1A2 genetika MeSH
- DNA primery MeSH
- epitelové buňky patologie účinky léků MeSH
- financování organizované MeSH
- játra cytologie účinky léků MeSH
- karbazoly toxicita MeSH
- karcinogeny toxicita MeSH
- krysa rodu rattus MeSH
- metylace MeSH
- molekulární struktura MeSH
- mutageny MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- potkani inbrední F344 MeSH
- sekvence nukleotidů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- acetyltransferasy genetika metabolismus MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 genetika metabolismus MeSH
- karbazoly farmakologie MeSH
- karcinogeny farmakologie metabolismus MeSH
- lidé MeSH
- poškození DNA účinky léků MeSH
- testy genotoxicity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
