SENCAR Mouse Skin Papillomas Induced by 6-Methylbenzo[a]pyrene Carry H-ras Codon 52 (CTALeu → CCAPro) and Codon 13 (GGCGly → GTCVal) Mutations

Chakravarti, Dhrubajyoti; Mailander, Paula C.; Cavalieri, Ercole L.; Rogan, Eleanor G.

doi:10.2174/1874372200701010006

Cited by 2 publications

(1 citation statement)

References 28 publications

(52 reference statements)

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“…Formation of high levels of DNA adducts in liver cells suggests that these compounds might have a systemic tumor-initiating activity. However, 6-MeBaP has been reported to produce only minimal level of papillomas in mice; therefore, the strong DNA adduct production in liver cells suggests that the 6-methyl derivative may be a tissue (liver)-specific genotoxin.…”

Section: Discussionmentioning

confidence: 99%

Toxic Effects of Methylated Benzo[a]pyrenes in Rat Liver Stem-Like Cells

Trilecová

Krčková²,

Marvanová³

et al. 2011

Chem. Res. Toxicol.

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The methylated benzo[a]pyrenes (MeBaPs) are present at significant levels in the environment, especially in the sediments contaminated by petrogenic PAHs. However, the existing data on their toxic effects in vitro and/or in vivo are still largely incomplete. Transcription factor AhR plays a key role in the metabolic activation of PAHs to genotoxic metabolites, but the AhR activation may also contribute to the tumor promoting effects of PAHs. In this study, the AhR-mediated activity of five selected MeBaP isomers was estimated in the DR-CALUX reporter gene assay performed in rat hepatoma cells. Detection of other effects, including induction of CYP1A1, CYP1B1, and AKR1C9 mRNAs, DNA adduct formation, production of reactive oxygen species, oxidation of deoxyguanosine, and cell cycle modulation and apoptosis, was performed in the rat liver epithelial WB-F344 cell line, a model of liver progenitor cells. We identified 1-MeBaP as the most potent inducer of AhR activation, stable DNA adduct formation, checkpoint kinase 1 and p53 phosphorylation, and apoptosis. These effects suggest that 1-MeBaP is a potent genotoxin eliciting a typical sequence of events ascribed to carcinogenic PAHs: induction of CYP1 enzymes, formation of high levels of DNA adducts, activation of DNA damage responses (including p53 phosphorylation), and cell death. In contrast, 10-MeBaP, representing BaP isomers substituted with the methyl group in the angular ring, elicited only low levels DNA adduct formation and apoptosis. Other MeBaPs under study also elicited strong apoptotic responses associated with DNA adduct formation as the prevalent mode of toxic action of these compounds in liver cells. MeBaPs induced a weak production of ROS, which did not lead to significant oxidative DNA damage. Importantly, 1-MeBaP and 3-MeBaP were found to be potent AhR agonists, one order of magnitude more potent than BaP, thus suggesting that the AhR-dependent modulations of gene expression, deregulation of cell survival mechanisms, and further nongenotoxic effects associated with AhR activation may further contribute to their tumor promotion and carcinogenicity.

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Section: Discussionmentioning

confidence: 99%

Toxic Effects of Methylated Benzo[a]pyrenes in Rat Liver Stem-Like Cells

Trilecová

Krčková²,

Marvanová³

et al. 2011

Chem. Res. Toxicol.

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Structure, function and carcinogenicity of metabolites of methylated and non-methylated polycyclic aromatic hydrocarbons: a comprehensive review

Flesher

Lehner

2016

Toxicology Mechanisms and Methods

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The Unified Theory of PAH Carcinogenicity accommodates the activities of methylated and non-methylated polycyclic aromatic hydrocarbons (PAHs) and states that substitution of methyl groups on meso-methyl substituted PAHs with hydroxy, acetoxy, chloride, bromide or sulfuric acid ester groups imparts potent cancer producing properties. It incorporates specific predictions from past researchers on the mechanism of carcinogenesis by methyl-substituted hydrocarbons, including (1) requirement for metabolism to an ArCH2X type structure where X is a good leaving group and (2) biological substitution of a meso-methyl group at the most reactive center in non-methylated hydrocarbons. The Theory incorporates strong inferences of Fieser: (1) The mechanism of carcinogenesis involves a specific metabolic substitution of a hydrocarbon at its most reactive center and (2) Metabolic elimination of a carcinogen is a detoxifying process competitive with that of carcinogenesis and occurring by a different mechanism. According to this outlook, chemical or biochemical substitution of a methyl group at the reactive meso-position of non-methylated hydrocarbons is the first step in the mechanism of carcinogenesis for most, if not all, PAHs and the most potent metabolites of PAHs are to be found among the meso methyl-substituted hydrocarbons. Some PAHs and their known or potential metabolites and closely related compounds have been tested in rats for production of sarcomas at the site of subcutaneous injection and the results strongly support the specific predictions of the Unified Theory.

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SENCAR Mouse Skin Papillomas Induced by 6-Methylbenzo[a]pyrene Carry H-ras Codon 52 (CTALeu → CCAPro) and Codon 13 (GGCGly → GTCVal) Mutations

Cited by 2 publications

References 28 publications

Toxic Effects of Methylated Benzo[a]pyrenes in Rat Liver Stem-Like Cells

Toxic Effects of Methylated Benzo[a]pyrenes in Rat Liver Stem-Like Cells

Structure, function and carcinogenicity of metabolites of methylated and non-methylated polycyclic aromatic hydrocarbons: a comprehensive review

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