O6-Pyridyloxobutylguanine Adducts Contribute to the Mutagenic Properties of Pyridyloxobutylating Agents

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• 作者：René ; e S. Mijal ; Natalia A. Loktionova ; Choua C. Vu ; Anthony E. Pegg ; and Lisa A. Peterson
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：October 2005
• 年：2005
• 卷：18
• 期：10
• 页码：1619 - 1625
• 全文大小：127K
• 年卷期：v.18,no.10(October 2005)
• ISSN：1520-5010

文摘

The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) andN'-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely humancarcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. Thisalkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation ofmiscoding DNA adducts. One of these adducts, O⁶-[4-oxo-4-(3-pyridyl)butyl]guanine (O⁶-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 protectscells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play asimilar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore,we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-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 ofO⁶-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct inNNKOAc-treated cultures. The levels of O⁶-pobG were lower in DNA from bacteria expressinghAGT. This work establishes an important role for O⁶-pobG in mediating the mutagenic, andpossibly carcinogenic, effects of pyridyloxobutylating compounds.