Effects of methylated chrysenes on AhR-dependent and -independent toxic events in rat liver epithelial cells
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
18407395
DOI
10.1016/j.tox.2008.02.008
PII: S0300-483X(08)00081-4
Knihovny.cz E-zdroje
- MeSH
- adukty DNA metabolismus MeSH
- buněčný cyklus účinky léků MeSH
- chryseny toxicita MeSH
- enzymová indukce účinky léků MeSH
- epitelové buňky účinky léků MeSH
- játra účinky léků MeSH
- karcinogeny toxicita MeSH
- krysa rodu Rattus MeSH
- mezerový spoj účinky léků MeSH
- mezibuněčná komunikace účinky léků MeSH
- receptory aromatických uhlovodíků fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 5-methylchrysene MeSH Prohlížeč
- 6-methylchrysene MeSH Prohlížeč
- adukty DNA MeSH
- chryseny MeSH
- karcinogeny MeSH
- receptory aromatických uhlovodíků 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.
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