Differences in DNA damage and repair produced by systemic, hepatocarcinogenic and sarcomagenic dibenzocarbazole derivatives in a model of rat liver progenitor cells.

Abstract

Liver progenitor (oval) cells are a potential target cell population for hepatocarcinogens. Our recent study showed that the liver carcinogens 7H-dibenzo[c,g]carbazole (DBC) and 5,9-dimethyldibenzo[c,g]carbazole (DiMeDBC), but not the sarcomagen N-methyldibenzo[c,g]carbazole (N-MeDBC), induced several cellular events associated with tumor promotion in WB-F344 cells, an in vitro model of liver oval cells [J. Vondracek, L. Svihalkova-Sindlerova, K. Pencikova, P. Krcmar, Z. Andrysik, K. Chramostova, S. Marvanova, Z. Valovicova, A. Kozubik, A. Gabelova, M. Machala, 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, Mutat. Res. Fundam. Mol. Mech. Mutagen. 596 (2006) 43-56]. In this study, we focused on the genotoxic effects generated by these dibenzocarbazoles in WB-F344 cells to better understand the cellular and molecular mechanisms involved in hepatocarcinogenesis. Lower IC(50) values determined for DBC and DiMeDBC, as compared with N-MeDBC, indicated a higher sensitivity of WB-F344 cells towards hepatocarcinogens. Accordingly, DBC produced a dose-dependent DNA-adduct formation resulting in substantial inhibition of DNA replication and transcription. In contrast, DNA-adduct number detected in DiMeDBC-exposed cells was almost negligible, whereas N-MeDBC produced a low level of DNA adducts. Although all dibenzocarbazoles significantly increased the level of strand breaks (p<0.05) and micronuclei (p<0.001) after 2-h treatment, differences in the kinetics of strand break rejoining were found. The strand break level in DiMeDBC- and N-MeDBC-exposed cells returned to near the background level within 24h after treatment, whereas a relatively high DNA damage level was detected in DBC-treated cells up to 48h after exposure. Additional breaks detected after incubation of DiMeDBC-exposed WB-F344 cells with a repair-specific endonuclease, along with a nearly 3-fold higher level of reactive oxygen species found in these cells as compared with control, suggest a possible role of oxidative stress in DiMeDBC genotoxicity. We demonstrated qualitative differences in the DNA damage profiles produced by hepatocarcinogens DBC and DiMeDBC in WB-F344 cells. Different lesions may trigger distinct cellular pathways involved in hepatocarcinogenesis. The low amount of DNA damage, together with an efficient repair, may explain the lack of hepatocarcinogenicity of N-MeDBC.

• Authors: Zuzana Valovicová, Sona Marvanová, Monika Mészárosová, Annamária Srancíková, Lenka Trilecová, Alena Milcová, Helena Líbalová, Jan Vondrácek, Miroslav Machala, Jan Topinka, Alena Gábelová
• Journal: Mutation research (Mutat Res) Vol. 665 Issue 1-2 Pg. 51-60 (Jun 01 2009) ISSN: 0027-5107 [Print] Netherlands
• PMID: 19427511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbazoles
• Carcinogens
• DNA Adducts
• Histones
• Mutagens
• 5,9-dimethyldibenzo(c,g)carbazole
• 7H-dibenzo(c,g)carbazole

Topics

• Animals
• Carbazoles (toxicity)
• Carcinogens (toxicity)
• Cell Line
• DNA Adducts (metabolism)
• DNA Damage
• DNA Repair
• Histones (metabolism)
• Kinetics
• Liver (cytology, drug effects, metabolism)
• Liver Neoplasms, Experimental (chemically induced)
• Models, Biological
• Mutagens (toxicity)
• Oxidative Stress (drug effects)
• Rats
• Sarcoma, Experimental (chemically induced)
• Stem Cells (cytology, drug effects, metabolism)