Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression.

Abstract

The goal of this study was to investigate the genotoxicity of 7H-dibenzo[c,g]carbazole (DBC), a ubiquitous environmental pollutant, and its methyl derivatives, 5,9-dimethylDBC (DiMeDBC), a strict hepatocarcinogen, and N-methylDBC (N-MeDBC), a specific sarcomagen in human hepatoma HepG2 cells, and to infer potential mechanisms underlying the biological activity of particular carcinogen. All dibenzocarbazoles, regardless the tissue specificity, induced significant DNA strand break levels and micronuclei in HepG2 cells; though a mitotic spindle dysfunction rather than a chromosome breakage was implicated in N-MeDBC-mediated micronucleus formation. While DBC and N-MeDBC produced stable DNA adducts followed with p53 protein phosphorylation at Ser-15, DiMeDBC failed. A significant increase in DNA strand breaks following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggested that either oxidative DNA damage or unstable DNA-adducts might underlie DiMeDBC genotoxicity in human hepatoma cells. DiMeDBC and N-MeDBC increased substantially also the amount of CYP1A1/2 expression in HepG2 cells. Pretreatment of cells with substances affecting AhR-mediated CYP1A family of enzymes expression; however, diminished DiMeDBC and N-MeDBC genotoxicity. Our data clearly demonstrated differences in the mechanisms involved in the biological activity of DiMeDBC and N-MeDBC in human hepatoma cells; the genotoxicity of these DBC derivatives is closely related to CYP1A1/2 expression.

• Authors: Alena Gábelová, Zuzana Valovičová, Monika Mesárošová, Lenka Trilecová, Eva Hrubá, Soňa Marvanová, Pavel Krčmár, Alena Milcová, Jana Schmuczerová, Jan Vondráček, Miroslav Machala, Jan Topinka
• Journal: Environmental and molecular mutagenesis (Environ Mol Mutagen) Vol. 52 Issue 8 Pg. 636-45 (Oct 2011) ISSN: 1098-2280 [Electronic] United States
• PMID: 21809388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley-Liss, Inc.

Chemical References

• Carbazoles
• DNA Adducts
• H2AX protein, human
• Histones
• Mutagens
• Tumor Suppressor Protein p53
• 5,9-dimethyldibenzo(c,g)carbazole
• CYP1A2 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2
• 7H-dibenzo(c,g)carbazole

Topics

• Base Sequence
• Blotting, Western
• Carbazoles (toxicity)
• Cell Survival (drug effects)
• Comet Assay
• Cytochrome P-450 CYP1A1 (genetics)
• Cytochrome P-450 CYP1A2 (genetics)
• DNA Adducts
• DNA Breaks
• Dose-Response Relationship, Drug
• Hep G2 Cells
• Histones (metabolism)
• Humans
• Micronuclei, Chromosome-Defective (chemically induced, statistics & numerical data)
• Micronucleus Tests
• Mitotic Index
• Molecular Sequence Data
• Mutagens (toxicity)
• Phosphorylation
• Real-Time Polymerase Chain Reaction
• Tumor Suppressor Protein p53 (metabolism)