Classical and molecular cytogenetics in analysis of diepoxybutane-induced chromosome aberrations

Sasiadek, Maria M.; Schlade, K; Busza, Halina; Czemarmazowicz, Halina; Stembalska, Agnieszka

doi:10.1016/s1383-5718(98)00131-4

Cited by 5 publications

(3 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although DEB is a relatively minor metabolite of BD, it is hypothesized to be the ultimate carcinogenic species of BD based on its proven genotoxic potency and the ability to induce bifunctional DNA adducts. ,− In previous studies, we have identified three types of DEB-specific DNA adducts, bis- N7G-BD, N7G-N1A-BD, and 1, N 6 -HMHP-dA, ,,, and developed quantitative HPLC-ESI-MS/MS methods for their analyses in tissues of laboratory rodents treated with BD by inhalation. ,, We found that immediately after BD exposure, bis- N7G-BD was the most abundant bifunctional adduct, followed by N7G-N1A-BD, and 1, N 6 -HMHP-dA, which were 15-fold and 100-fold less abundant, respectively (Table ) …”

Section: Discussionmentioning

confidence: 99%

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Goggin

Sangaraju

Walker

et al. 2011

Chem. Res. Toxicol.

View full text Add to dashboard Cite

1,3-butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen. The mechanism of BD-mediated cancer is of significant interest because of the widespread exposure of humans to BD from cigarette smoke and urban air. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is a highly genotoxic and mutagenic bis-alkylating agent believed to be the ultimate carcinogenic species of BD. We have previously identified several types of DEB-specific DNA adducts, including bis-N7-guanine cross-links (bis-N7-BD), N6-adenine-N7-guanine cross-links (N6A-N7G-BD), and 1,N6-dA exocyclic adducts. These lesions were detected in tissues of laboratory rodents exposed to BD by inhalation (Goggin et al. Cancer Res. 2009;69:2479–2486). In the present work, persistence and repair of bifunctional DEB-DNA adducts in tissues of mice and rats exposed to BD by inhalation were investigated. The half-lives of the most abundant cross-links, bis-N7G-BD, in mouse liver, kidney, and lungs were 2.3–2.4 days, 4.6–5.7 days, and 4.9 days, respectively. The in vitro half-lives of bis-N7G-BD were 3.5 days (S,S isomer) and 4.0 days (meso isomer) due to their spontaneous depurination. In contrast, tissue concentrations of the minor DEB adducts, N7G-N1A-BD and 1,N6-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t 1/2 of 36–42 days. No differences were observed between DEB-DNA adduct levels in BD-treated wild type mice and the corresponding animals deficient in methyl purine glycosylase or the Xpa gene. Our results indicate that DEB-induced N7G-N1A-BD and 1,N6-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure.

show abstract

Section: Discussionmentioning

confidence: 99%

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Goggin

Sangaraju

Walker

et al. 2011

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…1,2-Dibromoethane and diepoxybutane are both carcinogens in laboratory animals (3)(4)(5)(6)(7) and induce mutagenicity and toxicity in in vitro systems (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…Diepoxybutane is an oxidation product of the major industrial chemical butadiene, which is used in the synthesis of plastics and rubber, and found in automobile exhaust and cigarette smoke (). 1,2-Dibromoethane and diepoxybutane are both carcinogens in laboratory animals – and induce mutagenicity and toxicity in in vitro systems – .…”

Section: Introductionmentioning

confidence: 99%

Reactions of Glyceraldehyde 3-Phosphate Dehydrogenase Sulfhydryl Groups with Bis-Electrophiles Produce DNA–Protein Cross-Links but Not Mutations

Loecken

Guengerich

2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The environmental contaminant 1,2-dibromoethane and diepoxybutane, an oxidation product of the important industrial chemical butadiene, are bis-functional electrophiles and known to be mutagenic and carcinogenic. One mechanism by which bis-electrophiles can exert their toxic effects is through the induction of genotoxic and mutagenic DNA-peptide crosslinks. This mechanism has been shown in systems overexpressing the DNA repair protein O 6 -alkylguanine DNA-alkyltransferase (AGT) or glutathione S-transferase and involves reactions with nucleophilic cysteine residues. The hypothesis that DNA-protein crosslink formation is a more general mechanism for genotoxicity by bis-electrophiles was investigated by screening nuclear proteins for reactivity with model monofunctional electrophiles. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was identified as a candidate due to the nucleophilicity of two cysteine residues (Cys 152 and Cys 246 ) in reaction screens with model electrophiles (Dennehy, M. K. et al. (2006) Chem. Res. Toxicol. 19,[20][21][22][23][24][25][26][27][28][29]. Incubation of GAPDH with bis-electrophiles resulted in inhibition of its catalytic activity, but only at high concentrations of diepoxybutane. In vitro assays indicated DNA-GAPDH crosslink formation in the presence of diepoxybutane, and biselectrophile reactivity at Cys 246 was confirmed using mass spectral analysis. In contrast to AGT, overexpression of human GAPDH in Escherichia coli did not enhance mutagenesis by diepoxybutane. We propose that the lack of mutational enhancement is in part due to the inherently lower reactivity of GAPDH toward bis-electrophiles as well as the reduced DNA binding ability relative to AGT, preventing the in vivo formation of DNA-protein crosslinks and enhanced mutagenesis.

show abstract

Cytogenetic biomarkers in detection of genotoxic effects of gestagens in peripheral blood lymphocytes in vitro and in vivo

Grujičić

Radović

Arsenijevic

et al. 2016

European Journal of Medical Genetics

View full text Add to dashboard Cite

Classical and molecular cytogenetics in analysis of diepoxybutane-induced chromosome aberrations

Cited by 5 publications

References 26 publications

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Reactions of Glyceraldehyde 3-Phosphate Dehydrogenase Sulfhydryl Groups with Bis-Electrophiles Produce DNA–Protein Cross-Links but Not Mutations

Cytogenetic biomarkers in detection of genotoxic effects of gestagens in peripheral blood lymphocytes in vitro and in vivo

Contact Info

Product

Resources

About