Toxic effects of methylated benz[a]anthracenes in liver cells
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
18205319
DOI
10.1021/tx700305x
Knihovny.cz E-zdroje
- MeSH
- 9,10-dimethyl-1,2-benzanthracen chemie metabolismus toxicita MeSH
- adukty DNA analýza metabolismus MeSH
- apoptóza účinky léků MeSH
- benz(a)anthraceny chemie metabolismus toxicita MeSH
- DNA účinky léků metabolismus MeSH
- enzymová indukce MeSH
- hepatocelulární karcinom MeSH
- hepatocyty účinky léků metabolismus patologie MeSH
- kmenové buňky účinky léků metabolismus patologie MeSH
- krysa rodu Rattus MeSH
- messenger RNA metabolismus MeSH
- metylace MeSH
- mezerový spoj účinky léků MeSH
- nádorové buněčné linie MeSH
- nádory jater MeSH
- potkani inbrední F344 MeSH
- proliferace buněk účinky léků MeSH
- regulace genové exprese enzymů účinky léků MeSH
- reportérové geny účinky léků MeSH
- systém (enzymů) cytochromů P-450 genetika metabolismus 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
- 6-methylbenz(a)anthracene MeSH Prohlížeč
- 9,10-dimethyl-1,2-benzanthracen MeSH
- adukty DNA MeSH
- benz(a)anthracene MeSH Prohlížeč
- benz(a)anthraceny MeSH
- DNA MeSH
- messenger RNA MeSH
- systém (enzymů) cytochromů P-450 MeSH
Monomethylated benz[ a]anthracenes (MeBaAs) are an important group of methylated derivatives of polycyclic aromatic hydrocarbons (PAHs). Although the methyl substitution reportedly affects their mutagenicity and tumor-initiating activity, little is known about the impact of methylation on the effects associated with activation of the aryl hydrocarbon receptor (AhR)-dependent gene expression and/or toxic events associated with tumor promotion. In the present study, we studied the effects of a series of MeBaAs on the above-mentioned end points in rat liver cell lines and compared them with the effects of benz[ a]anthracene (BaA) and the potent carcinogen 7,12-dimethylbenz[ a]anthracene (DMBA). Methyl substitution enhanced the AhR-mediated activity of BaA derivatives determined in a reporter gene assay, as the induction equivalency factors (IEFs) of all MeBaAs were higher than that of BaA. IEFs of 6-MeBaA and 9-MeBaA, two of the most potent MeBaAs, were more than two orders of magnitude higher than the IEF of BaA. Correspondingly, all MeBaAs induced higher levels of cytochrome P450 1A1 mRNA. Both BaA and MeBaAs had similar effects on the expression of cytochrome P450 1B1 or aldo-keto reductase 1C9 in rat liver epithelial WB-F344 cells. In contrast to genotoxic DMBA, MeBaAs induced low DNA adduct formation. Only 10-MeBaA induced apoptosis and accumulation of phosphorylated p53, which could be associated with the induction of oxidative stress, similar to DMBA. With the exception of 10-MeBaA, all MeBaAs induced cell proliferation in contact-inhibited WB-F344 cells, which corresponded with their ability to activate AhR. 1-, 2-, 8-, 10-, 11-, and 12-MeBaA inhibited gap junctional intercellular communication (GJIC) in WB-F344 cells. This mode of action, like disruption of cell proliferation control, might contribute to tumor promotion. Taken together, these data showed that the methyl substitution significantly influences those effects of MeBaAs associated with AhR activation or GJIC inhibition.
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