Induction of micronuclei by 7H-dibenzo[c,g]carbazole and its tissue specific derivatives in Chinese hamster V79MZh1A1 cells

Farkašová, Timea; Gábelová, Alena; Slameñová, D

doi:10.1016/s1383-5718(01)00127-9

Cited by 13 publications

(5 citation statements)

References 35 publications

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“…Based on our preliminary experiments, concentrations ranging from 0 to 2.5 µM were selected for B[ a ]P, DBC, and its derivatives in this study. Consistent with our previous results [Gabelova et al, , ; Farkasova et al, ; Valovicova et al, ], the cytotoxicity of B[ a ]P and of individual DBC derivatives was relatively low or negligible at these concentrations (Figs. A, C, D, and E).…”

Section: Resultssupporting

confidence: 93%

Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7H‐dibenzo[c,g]carbazole and its methyl derivatives

Sedláčková

Bábelová

Kozics

et al. 2014

Environ and Mol Mutagen

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7H-Dibenzo[c,g]carbazole (DBC) is a heterocyclic aromatic hydrocarbon that is carcinogenic in many species and tissues. DBC is a common environmental pollutant, and is therefore constantly exposed to sunlight. However, there are limited data exploring the toxicity of DBC photoexcitation products. Here, we investigated the impact of ultraviolet (UV) A radiation on the biological activity of DBC and its methyl derivatives, 5,9-dibenzo[c,g]carbazole and N-methyl dibenzo[c,g]carbazole, on human skin HaCaT keratinocytes. Co-exposure of HaCaT cells to UVA and DBC derivatives resulted in a sharp dose-dependent decrease in cell survival and apparent changes in cell morphology. Under the same treatment conditions, significant increases in DNA strand breaks, intracellular reactive oxygen species, and oxidative damage to DNA were observed in HaCaT cells. Consistent with these results, an apparent inhibition in superoxide dismutase, but not glutathione peroxidase activity, was detected in cells treated with DBC and its derivatives under UVA irradiation. The photoactivation-induced toxicity of individual DBC derivatives correlated with the electron excitation energies approximately expressed as the energy difference between the highest occupied and the lowest vacant molecular orbital. Our data provide the first evidence that UVA can enhance the toxicity of DBC and its derivatives. Photoactivation-induced conversion of harmless chemical compounds to toxic photoproducts associated with reactive oxygen species generation may substantially amplify the adverse health effects of UVA radiation and contribute to increased incidence of skin cancer.

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Section: Resultssupporting

confidence: 93%

Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7H‐dibenzo[c,g]carbazole and its methyl derivatives

Sedláčková

Bábelová

Kozics

et al. 2014

Environ and Mol Mutagen

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“…Although 32 P postlabeling revealed one weak DNA adduct in diMeDBC-treated V79MZh1A1 cells (Fig. 2), previous studies indicated that diMeDBC induced neither gene mutations nor micronuclei in these cells [Farkasová et al, 2001;Gábelová et al, 2002]. In vivo experiments demonstrated a clear correlation between the DNA-binding capacity of tissue-specific DBC derivatives and their ability to induce tumors in particular tissues Renault et al, 1998;Taras-Valéro et al, 2000].…”

Section: Discussionmentioning

confidence: 73%

“…The use of genetically engineered Chinese hamster V79 cell lines with stable expression of single CYP enzymes revealed a role for CYP1A1 in the metabolic activation of sarcomagenic DBC derivatives [Gábelová et al, 2000]. Activation of DBC and MeDBC via CYP1A1 resulted in MN formation and gene mutations [Farkasová et al, 2001;Gábelová et al, 2002]. Using a similar exposure protocol, several stable 32 P-postlabeled DNA adducts were detected in V79MZh1A1 cells exposed to DBC and MeDBC (Fig.…”

Section: Discussionmentioning

confidence: 89%

“…Using genetically engineered Chinese hamster V79 cell lines with stable expression of individual CYP isoforms, it was shown that CYP1A1 is specifically involved in biotransformation of DBC derivatives with sarcomagenic activity. DBC and MeDBC produced significant increases in the levels of micronuclei and gene mutations, while the organ-specific hepatocarcinogen diMeDBC was devoid of any activity in these cells [Gábelová et al, 2000;Farkasová et al, 2001]. Also, DBC, MeDBC, and diMeDBC all produced significant increases in gene mutation in the V79MZh1A2 cell line expressing human CYP1A2 [Gábelová et al, 2002], suggesting that CYP1A2 is involved in the metabolic activation of both the sarcomagenic and hepatocarcinogenic DBC derivatives.…”

Section: Introductionmentioning

confidence: 99%

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DNA adduct formation by 7H‐dibenzo[c,g]carbazole and its tissue‐ and organ‐specific derivatives in Chinese hamster V79 cell lines stably expressing cytochrome P450 enzymes

Gábelová¹,

Binková²,

Valovičová³

et al. 2004

Environ and Mol Mutagen

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The cytochrome P4501A subfamily (CYP1A) is involved in the metabolic activation of 7H-dibenzo[c,g]carbazole (DBC) and its tissue- and organ-specific derivatives, N-methyldibenzo[c,g]carbazole (MeDBC)and 5,9-dimethyldibenzo[c,g]carbazole (diMeDBC). In this study, we have evaluated the relationship between the tissue specificity and (32)P-postlabeled adduct patterns produced by these compounds by using a panel of Chinese hamster V79 cell lines stably expressing human CYP1A1 and CYP1A2 and/or N-acetyltransferase. Treatment of the parental cell lines V79MZ and V79NH, which are devoid of any CYP activity, with DBC and its derivatives did not result in detectable adducts. The highest DNA adduct levels were found in CYP1A1-expressing V79MZh1A1 cells after DBC and MeDBC treatment (24.5 +/- 7.2 and 16.2 +/- 3.6 adducts/10(8) nucleotides, respectively). Exposure of this cell line to DBC resulted in five distinct spots, while six spots with different chromatographic mobilities were detected in MeDBC-treated cells. DiMeDBC produced only very low levels of DNA adducts in V79MZh1A1 cells. DBC and MeDBC formed relatively low levels of DNA adducts in CYP1A2-expressing V79MZh1A2 cells (0.7 +/- 0.2 and 2.1 +/- 1.2 adducts/10(8) nucleotides, respectively). DBC formed three weak spots and MeDBC five spots in V79MZh1A2 cells, and all the spots had different chromatographic mobilities. In contrast, diMeDBC did not induce any DNA adducts in these cells, although diMeDBC induced a significant dose-dependent increase in micronucleus frequency under similar treatment conditions (r = 0.76; P < 0.001). The significant increase in DNA damage in the Comet assay following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggests that base modifications such as 8-oxodG or Fapy-adducts might be responsible for the genotoxicity of diMeDBC in V79MZh1A2 cells. The similarities between the DNA adduct patterns produced by DBC and MeDBC in V79MZh1A1 and V79MZh1A2 cells suggest that biotransformation mediated via CYP1A1 and CYP1A2 might depend on a PAH-type pathway involving the aromatic ring system.

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“…Consistent with these results, DiMeDBC and mainly N-MeDBC increased substantially the CYP1A1/2 mRNA levels in HepG2 cells. Previous in vitro studies convincingly demonstrated that human CYP1A1 and CYP1A2 are involved in metabolism of DBC and its tissue-specific derivatives [Gabelova et al, 1998[Gabelova et al, , 2000[Gabelova et al, , 2004Farkasova et al, 2001;Shertzer et al, 2007]. The CYP1A1/2-mediated N-MeDBC and DBC activation resulted in DNA breakage, increased frequency of micronuclei, DNA-adduct formation, and induction of gene mutations.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

Gábelová

Valovičová

Mesárošová

et al. 2011

Environ. Mol. Mutagen.

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The goal of this study was to investigate the genotoxicity of 7H-dibenzo[c,g]carbazole (DBC), a ubiquitous environmental pollutant, and its methyl derivatives, 5,9-dimethylDBC (DiMeDBC), a strict hepatocarcinogen, and N-methylDBC (N-MeDBC), a specific sarcomagen in human hepatoma HepG2 cells, and to infer potential mechanisms underlying the biological activity of particular carcinogen. All dibenzocarbazoles, regardless the tissue specificity, induced significant DNA strand break levels and micronuclei in HepG2 cells; though a mitotic spindle dysfunction rather than a chromosome breakage was implicated in N-MeDBC-mediated micronucleus formation. While DBC and N-MeDBC produced stable DNA adducts followed with p53 protein phosphorylation at Ser-15, DiMeDBC failed. A significant increase in DNA strand breaks following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggested that either oxidative DNA damage or unstable DNA-adducts might underlie DiMeDBC genotoxicity in human hepatoma cells. DiMeDBC and N-MeDBC increased substantially also the amount of CYP1A1/2 expression in HepG2 cells. Pretreatment of cells with substances affecting AhR-mediated CYP1A family of enzymes expression; however, diminished DiMeDBC and N-MeDBC genotoxicity. Our data clearly demonstrated differences in the mechanisms involved in the biological activity of DiMeDBC and N-MeDBC in human hepatoma cells; the genotoxicity of these DBC derivatives is closely related to CYP1A1/2 expression.

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Induction of micronuclei by 7H-dibenzo[c,g]carbazole and its tissue specific derivatives in Chinese hamster V79MZh1A1 cells

Cited by 13 publications

References 35 publications

Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7H‐dibenzo[c,g]carbazole and its methyl derivatives

Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7H‐dibenzo[c,g]carbazole and its methyl derivatives

DNA adduct formation by 7H‐dibenzo[c,g]carbazole and its tissue‐ and organ‐specific derivatives in Chinese hamster V79 cell lines stably expressing cytochrome P450 enzymes

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

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