Activation of bis-electrophiles to mutagenic conjugates by human O 6-alkylgvanine-DNA alkyltransferase

J. Gerardo Valadez, Liping Liu, Natalia A. Loktionova, Anthony Pegg, F. Peter Guengerich

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

O6-Alkylguanine DNA-alkyl transferase (AGT) has been shown to conjugate both 1,2-dibromoethane and dibromomethane, yielding AGT inactivation, DNA-AGT cross-linking, and enhanced mutagenicity. A variety of related chemicals were examined to determine if similar phenomena occur. Among the compounds examined in these systems (histidine operon reversion in Escherichia coli and Salmonella typhimurium tester strains), a strong halide order was generally observed, with increasing activities in the order I > Br ≫ Cl. At least one Br atom appeared to be required for human AGT-dependent mutations, and compounds with only Cl did not inhibit AGT and were not activated to genotoxins. Of a series of haloforms tested (CHX3, X = Br or Cl), all were without effect. Among a series of α,ω-disubstituted dihaloalkanes (Br or I), the inactivation of AGT increased with methylene chain length (at least up to n = 5) but the most mutagenic activity (AGT-dependent) was seen with n = 1-3. The effects with n = 1 or 2 were expected from previous results; the mutagenic effect with n = 3 and the reduction with n > 3 may represent a balance between AGT reaction, stability, and reactivity, in the absence of anchimeric assistance. A strong AGT-dependent mutation was observed for 1,3-butadiene diepoxide. We conclude that numerous bis-electrophiles show AGT-dependent activation to mutagenic conjugates. Haloforms and dichloroalkanes are therefore not an issue, but bromohaloalkanes and 1,3-butadiene diepoxide are potential problems. These observations are of relevance in considering toxicity and risks of some chemicals used in industrial applications.

Original languageEnglish (US)
Pages (from-to)972-982
Number of pages11
JournalChemical research in toxicology
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2004

Fingerprint

Ethylene Dibromide
Chemical activation
Mutation
Salmonella
DNA
Mutagens
Salmonella typhimurium
Operon
Transferases
Chain length
Histidine
Escherichia coli
Industrial applications
Toxicity
Atoms
1,3-butadiene diepoxide
DNA alkyltransferase
methylene bromide

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Valadez, J. Gerardo ; Liu, Liping ; Loktionova, Natalia A. ; Pegg, Anthony ; Guengerich, F. Peter. / Activation of bis-electrophiles to mutagenic conjugates by human O 6-alkylgvanine-DNA alkyltransferase. In: Chemical research in toxicology. 2004 ; Vol. 17, No. 7. pp. 972-982.
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abstract = "O6-Alkylguanine DNA-alkyl transferase (AGT) has been shown to conjugate both 1,2-dibromoethane and dibromomethane, yielding AGT inactivation, DNA-AGT cross-linking, and enhanced mutagenicity. A variety of related chemicals were examined to determine if similar phenomena occur. Among the compounds examined in these systems (histidine operon reversion in Escherichia coli and Salmonella typhimurium tester strains), a strong halide order was generally observed, with increasing activities in the order I > Br ≫ Cl. At least one Br atom appeared to be required for human AGT-dependent mutations, and compounds with only Cl did not inhibit AGT and were not activated to genotoxins. Of a series of haloforms tested (CHX3, X = Br or Cl), all were without effect. Among a series of α,ω-disubstituted dihaloalkanes (Br or I), the inactivation of AGT increased with methylene chain length (at least up to n = 5) but the most mutagenic activity (AGT-dependent) was seen with n = 1-3. The effects with n = 1 or 2 were expected from previous results; the mutagenic effect with n = 3 and the reduction with n > 3 may represent a balance between AGT reaction, stability, and reactivity, in the absence of anchimeric assistance. A strong AGT-dependent mutation was observed for 1,3-butadiene diepoxide. We conclude that numerous bis-electrophiles show AGT-dependent activation to mutagenic conjugates. Haloforms and dichloroalkanes are therefore not an issue, but bromohaloalkanes and 1,3-butadiene diepoxide are potential problems. These observations are of relevance in considering toxicity and risks of some chemicals used in industrial applications.",
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Activation of bis-electrophiles to mutagenic conjugates by human O 6-alkylgvanine-DNA alkyltransferase. / Valadez, J. Gerardo; Liu, Liping; Loktionova, Natalia A.; Pegg, Anthony; Guengerich, F. Peter.

In: Chemical research in toxicology, Vol. 17, No. 7, 01.07.2004, p. 972-982.

Research output: Contribution to journalArticle

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T1 - Activation of bis-electrophiles to mutagenic conjugates by human O 6-alkylgvanine-DNA alkyltransferase

AU - Valadez, J. Gerardo

AU - Liu, Liping

AU - Loktionova, Natalia A.

AU - Pegg, Anthony

AU - Guengerich, F. Peter

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N2 - O6-Alkylguanine DNA-alkyl transferase (AGT) has been shown to conjugate both 1,2-dibromoethane and dibromomethane, yielding AGT inactivation, DNA-AGT cross-linking, and enhanced mutagenicity. A variety of related chemicals were examined to determine if similar phenomena occur. Among the compounds examined in these systems (histidine operon reversion in Escherichia coli and Salmonella typhimurium tester strains), a strong halide order was generally observed, with increasing activities in the order I > Br ≫ Cl. At least one Br atom appeared to be required for human AGT-dependent mutations, and compounds with only Cl did not inhibit AGT and were not activated to genotoxins. Of a series of haloforms tested (CHX3, X = Br or Cl), all were without effect. Among a series of α,ω-disubstituted dihaloalkanes (Br or I), the inactivation of AGT increased with methylene chain length (at least up to n = 5) but the most mutagenic activity (AGT-dependent) was seen with n = 1-3. The effects with n = 1 or 2 were expected from previous results; the mutagenic effect with n = 3 and the reduction with n > 3 may represent a balance between AGT reaction, stability, and reactivity, in the absence of anchimeric assistance. A strong AGT-dependent mutation was observed for 1,3-butadiene diepoxide. We conclude that numerous bis-electrophiles show AGT-dependent activation to mutagenic conjugates. Haloforms and dichloroalkanes are therefore not an issue, but bromohaloalkanes and 1,3-butadiene diepoxide are potential problems. These observations are of relevance in considering toxicity and risks of some chemicals used in industrial applications.

AB - O6-Alkylguanine DNA-alkyl transferase (AGT) has been shown to conjugate both 1,2-dibromoethane and dibromomethane, yielding AGT inactivation, DNA-AGT cross-linking, and enhanced mutagenicity. A variety of related chemicals were examined to determine if similar phenomena occur. Among the compounds examined in these systems (histidine operon reversion in Escherichia coli and Salmonella typhimurium tester strains), a strong halide order was generally observed, with increasing activities in the order I > Br ≫ Cl. At least one Br atom appeared to be required for human AGT-dependent mutations, and compounds with only Cl did not inhibit AGT and were not activated to genotoxins. Of a series of haloforms tested (CHX3, X = Br or Cl), all were without effect. Among a series of α,ω-disubstituted dihaloalkanes (Br or I), the inactivation of AGT increased with methylene chain length (at least up to n = 5) but the most mutagenic activity (AGT-dependent) was seen with n = 1-3. The effects with n = 1 or 2 were expected from previous results; the mutagenic effect with n = 3 and the reduction with n > 3 may represent a balance between AGT reaction, stability, and reactivity, in the absence of anchimeric assistance. A strong AGT-dependent mutation was observed for 1,3-butadiene diepoxide. We conclude that numerous bis-electrophiles show AGT-dependent activation to mutagenic conjugates. Haloforms and dichloroalkanes are therefore not an issue, but bromohaloalkanes and 1,3-butadiene diepoxide are potential problems. These observations are of relevance in considering toxicity and risks of some chemicals used in industrial applications.

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