Carcinogenicity and toxicity of 1,2-dibromoethane in the rat

Wong, Laurence; Winston, Joseph M.; Hong, Chuen-Bin; Plotnick, Harry B.

doi:10.1016/0041-008x(82)90036-9

Cited by 87 publications

(34 citation statements)

References 19 publications

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“…Mice exposed to DCM have a marked increase in the incidence of tumours of the lung and the liver [16,17]. The carcinogenicity of DCM requires its metabolic activation by GST, catalysing a nucleophilic substitution of chloride for the stabilized glutathione thiolate ion.…”

Section: Discussionmentioning

confidence: 99%

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Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of dichloromethane, a liver and lung carcinogen in the mouse: Comparison of the tissue distribution of GST T1-1 with that of classes Alpha, Mu and Pi GST in human

Sherratt

Pulford

Harrison

et al. 1997

Biochemical Journal

136

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The cDNA encoding human glutathione S-transferase (GST) T1 has been expressed as two recombinant forms in Escherichia coli that could be purified by affinity chromatography on either IgGSepharose or nickel-agarose ; one form of the transferase was synthesized from the pALP 1 expression vector as a Staphylococcus aureus protein A fusion, whereas the other form was synthesized from the pET-20b expression vector as a C-terminal polyhistidine-tagged recombinant. The yields of the two purified recombinant proteins from E. coli cultures were approx. 15 mg\l for the protein A fusion and 25 mg\l for the C-terminal polyhistidine-tagged GST T1-1. The purified recombinant proteins were catalytically active, although the protein A fusion was typically only 5-30 % as active as the histidine-tagged GST. Both recombinant forms could catalyse the conjugation of glutathione with the model substrates 1,2-epoxy-3-(4h-

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Section: Discussionmentioning

confidence: 99%

“…[ [14][15][16][17], and the epoxide-containing 1,2-epoxy-4-bromobutane and butadiene diepoxide [18,19]. Certain of the chemicals that are activated by GST are widely distributed in the environment ; there is therefore justified concern about the risk they pose to human health.…”

Section: Introductionmentioning

confidence: 99%

Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of dichloromethane, a liver and lung carcinogen in the mouse: Comparison of the tissue distribution of GST T1-1 with that of classes Alpha, Mu and Pi GST in human

Sherratt

Pulford

Harrison

et al. 1997

Biochemical Journal

136

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“…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%

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.

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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.

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“…The protocol used was: DBE by gavage either four times (60 mg/kg) or once (120 mg/kg), a partial hepatectomy to stimulate cell replication, a promotional regimen of 500 ppm phenobarbital in drinking water, and sacrifice at 67 days. DBE (also known as ethylene dibromide or EDB) is considered a potent carcinogen because carcinomas develop in a high percentage of rodents repeatedly exposed to DBE by gavage, inhalation or topical application (Weisburger 1977;van Duuren et al 1979;NTP/NCI 1982;Wong et al 1982). The carcinomas developed chiefly at the sites of DBE exposure and the incidence of liver cancers or nodules was lower.…”

Section: Introductionmentioning

confidence: 97%

1,2-Dibromoethane initiation of hepatic nodules in Sprague-Dawley rats selected with Solt-Farber system

1985

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Initiating effects of the fumigant 1,2-dibromoethane (DBE) for liver were examined using the Solt-Farber selection system. Male Sprague Dawley rats (230-260 g) were given one oral dose of DBE (75 mg/kg), a two-thirds partial hepatectomy 4 h later, five oral doses of 2-acetylamidofluorene (AAF) (25 mg/kg) on days 17-21, CCl4 (2 ml/kg) on day 22, a booster dose of AAF (10 mg/kg) on day 32, and were sacrificed on day 82. Nodules and appreciable gamma-glutamyl transpeptidase foci were found in the livers of four of six animals given DBE, but not in any animals of the control group.

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Carcinogenicity and toxicity of 1,2-dibromoethane in the rat

Cited by 87 publications

References 19 publications

Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of dichloromethane, a liver and lung carcinogen in the mouse: Comparison of the tissue distribution of GST T1-1 with that of classes Alpha, Mu and Pi GST in human

Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of dichloromethane, a liver and lung carcinogen in the mouse: Comparison of the tissue distribution of GST T1-1 with that of classes Alpha, Mu and Pi GST in human

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

1,2-Dibromoethane initiation of hepatic nodules in Sprague-Dawley rats selected with Solt-Farber system

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