Effects of methylated chrysenes on AhR-dependent and -independent toxic events in rat liver epithelial cells
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18407395
DOI
10.1016/j.tox.2008.02.008
PII: S0300-483X(08)00081-4
Knihovny.cz E-resources
- MeSH
- DNA Adducts metabolism MeSH
- Cell Cycle drug effects MeSH
- Chrysenes toxicity MeSH
- Enzyme Induction drug effects MeSH
- Epithelial Cells drug effects MeSH
- Liver drug effects MeSH
- Carcinogens toxicity MeSH
- Rats MeSH
- Gap Junctions drug effects MeSH
- Cell Communication drug effects MeSH
- Receptors, Aryl Hydrocarbon physiology MeSH
- Dose-Response Relationship, Drug 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-methylchrysene MeSH Browser
- 6-methylchrysene MeSH Browser
- DNA Adducts MeSH
- Chrysenes MeSH
- Carcinogens MeSH
- Receptors, Aryl Hydrocarbon MeSH
Methylated chrysenes (MeChry) are important cigarette smoke constituents and 5-MeChry has been listed as possibly carcinogenic to humans. Although a major attention has been in past paid especially to mutagenic, tumor-initiating effects of MeChry, little is known about toxic effects of MeChry related to tumor promotion. As the position of methyl group has been repeatedly observed to determine genotoxic effects of MeChry, we examined both genotoxic and nongenotoxic effects of MeChry, using rat liver cell lines as experimental models. All six MeChry were relatively efficient aryl hydrocarbon receptor (AhR) agonists, with 3- and 6-MeChry being the most potent inducers of the AhR-mediated reporter gene activity. All six compounds disrupted contact inhibition in rat liver epithelial WB-F344 cells, a process previously reported to be AhR-dependent, suggesting that MeChry may interfere with cell cycle control in an AhR-dependent manner. In contrast, only 5- and 6-MeChry were found to acutely inhibit gap junctional intercellular communication (GJIC), another parameter correlating with tumor promoting effects of xenobiotics. Both 5- and 6-MeChry were efficient inducers of mRNA expression of enzymes involved in metabolic activation of polycyclic aromatic hydrocarbons, including cytochromes P450 1A1/1B1 and aldo-keto reductase 1C9. However, only 5-MeChry, and not 6-MeChry, induced significant formation of DNA adducts in rat liver epithelial cells, which corresponded with its ability to induce high accumulation of cells in S-phase. On the other hand, 5-MeChry induced neither apoptosis related to DNA damage nor phosphorylation of p53 tumor suppressor. Taken together, our results suggest that methyl group position may affect both genotoxic and nongenotoxic effects of MeChry, such as formation of DNA adducts and inhibition of GJIC. All MeChry showed a potency to disrupt cell proliferation control, while 5-MeChry was a single compound inducing DNA damage, disruption of cell cycle control and inhibition of GJIC in rat liver cells.
References provided by Crossref.org
Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing