Synthesis of Depurinating DNA Adducts Formed by One-Electron Oxidation of 7<i>H</i>-Dibenzo[<i>c,g</i>]carbazole and Identification of These Adducts after Activation with Rat Liver Microsomes

Chen, Liang; Devanesan, Prabu; Byun, Jaeman; Gooden, Jonathan K.; Gross, Michael L.; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1021/tx960149h

Cited by 28 publications

(23 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A significant level of Fpg-sensitive sites detected in DiMeDBC-treated cells suggest that either oxidative DNA damage or unstable DNA adducts formed by one-electron oxidation [Chen et al, 1997] might underlie the biological activity of DiMeDBC in human hepatoma cells. Our results are in line with previous ones determined in the rat progenitor WB-F344 cells [Valovicova et al, 2009] and in the Chinese hamster V79MZh1A2 cells [Gabelova et al, 2004].…”

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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…Chen et al [1997] have demonstrated that DBC forms unstable depurinating DNA adducts through radical cations generated by one-electron oxidation. With DBC, this biotransformation pathway is supposed to be only a minor one [Dowty et al, 2000].…”

Section: Discussionmentioning

confidence: 99%

“…Although DBC, which has a relatively low ionization potential [Xue et al, 1999], can form depurinated DNA adducts through radical cations by one-electron oxidation [Chen et al, 1997], this mechanism is a minor metabolic pathway in mouse liver and lung [Dowty et al, 2000]. Recently, Xue et al [2002] have presented a potential metabolic activation mechanism of DBC via an o-quinone that results in both stable and depurinating DNA adduct formation.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…The human cytochrome P450 1A (CYP1) and 3A (CYP3A) families of enzymes have been shown to be involved in DBC biotransformation [Mesarosova et al, ; Valovicova et al, ; Gabelova et al, ] and the monohydroxylated derivatives are the major DBC metabolites [Warshawsky et al, ]. Because of a relatively low ionization potential, the radical‐cation can also be involved in DBC metabolism via one‐electron oxidation, though it may represent only a minor metabolic pathway [Chen et al, ; Dowty et al, ]. In addition, DBC undergoes aldo‐keto reductase‐catalyzed oxidation, and DBC‐3,4‐dione is supposed to be the ultimate metabolite of this carcinogen [Xue et al, ].…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Synthesis of Depurinating DNA Adducts Formed by One-Electron Oxidation of 7H-Dibenzo[c,g]carbazole and Identification of These Adducts after Activation with Rat Liver Microsomes

Cited by 28 publications

References 34 publications

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

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

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

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

Contact Info

Product

Resources

About