O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents.
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 (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 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-(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 of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O6-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.
Division of Environmental Health Sciences and The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Renée S
RS
Mijal
Natalia A
NA
Loktionova
Choua C
CC
Vu
Anthony E
AE
Pegg
Lisa A
LA
Peterson
D000477:Alkylating Agents / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D006801:Humans; D009152:Mutagenicity Tests; D009602:Nitrosamines / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D014162:Transfection
D000477:Alkylating Agents; D018736:DNA Adducts; D009602:Nitrosamines; C473029:O(6)-(4-oxo-4-(3-pyridyl)butyl)guanine; D011725:Pyridines; C081510:4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone; D006147:Guanine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase