title: Toxic effects of methylated benz[a]anthracenes in liver cells.
abstract: 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.
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Marvanová
authors.forename: Jan
authors.initials: J
authors.lastname: Vondrácek
authors.forename: Katerrina
authors.initials: K
authors.lastname: Penccíková
authors.forename: Lenka
authors.initials: L
authors.lastname: Trilecová
authors.forename: Pavel
authors.initials: P
authors.lastname: Krcmárr
authors.forename: Jan
authors.initials: J
authors.lastname: Topinka
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Nováková
authors.forename: Alena
authors.initials: A
authors.lastname: Milcová
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001551:Benz(a)Anthracenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D017629:Gap Junctions / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms; D008745:Methylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D001551:Benz(a)Anthracenes; D018736:DNA Adducts; D012333:RNA, Messenger; C046305:6-methylbenz(a)anthracene; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene