Toxic effects of methylated benz[a]anthracenes in liver cells
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18205319
DOI
10.1021/tx700305x
Knihovny.cz E-resources
- MeSH
- 9,10-Dimethyl-1,2-benzanthracene chemistry metabolism toxicity MeSH
- DNA Adducts analysis metabolism MeSH
- Apoptosis drug effects MeSH
- Benz(a)Anthracenes chemistry metabolism toxicity MeSH
- DNA drug effects metabolism MeSH
- Enzyme Induction MeSH
- Carcinoma, Hepatocellular MeSH
- Hepatocytes drug effects metabolism pathology MeSH
- Stem Cells drug effects metabolism pathology MeSH
- Rats MeSH
- RNA, Messenger metabolism MeSH
- Methylation MeSH
- Gap Junctions drug effects MeSH
- Cell Line, Tumor MeSH
- Liver Neoplasms MeSH
- Rats, Inbred F344 MeSH
- Cell Proliferation drug effects MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Genes, Reporter drug effects MeSH
- Cytochrome P-450 Enzyme System genetics metabolism 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
- 6-methylbenz(a)anthracene MeSH Browser
- 9,10-Dimethyl-1,2-benzanthracene MeSH
- DNA Adducts MeSH
- benz(a)anthracene MeSH Browser
- Benz(a)Anthracenes MeSH
- DNA MeSH
- RNA, Messenger MeSH
- Cytochrome P-450 Enzyme System 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.
References provided by Crossref.org
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