O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents

Renée S. Mijal, Natalia A. Loktionova, Choua C. Vu, Anthony Pegg, Lisa A. Peterson

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and N′-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O 6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1- butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O 6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.

Original languageEnglish (US)
Pages (from-to)1619-1625
Number of pages7
JournalChemical Research in Toxicology
Volume18
Issue number10
DOIs
StatePublished - Oct 1 2005

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N'-nitrosonornicotine
Repair
Alkylating Agents
Carcinogens
Bacteria
Butanones
Nitrosamines
Salmonella
Tobacco
DNA Adducts
Salmonella typhimurium
Shielding
Toxicity
Animals
Animal Models
DNA
Substrates
4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone
Proteins

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Mijal, Renée S. ; Loktionova, Natalia A. ; Vu, Choua C. ; Pegg, Anthony ; Peterson, Lisa A. / O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents. In: Chemical Research in Toxicology. 2005 ; Vol. 18, No. 10. pp. 1619-1625.
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abstract = "The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and N′-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O 6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1- butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O 6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.",
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O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents. / Mijal, Renée S.; Loktionova, Natalia A.; Vu, Choua C.; Pegg, Anthony; Peterson, Lisa A.

In: Chemical Research in Toxicology, Vol. 18, No. 10, 01.10.2005, p. 1619-1625.

Research output: Contribution to journalArticle

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T1 - O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents

AU - Mijal, Renée S.

AU - Loktionova, Natalia A.

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AU - Pegg, Anthony

AU - Peterson, Lisa A.

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N2 - The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and N′-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O 6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1- butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O 6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.

AB - The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and N′-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O 6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1- butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O 6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.

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