The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), a human carcinogen, is metabolized to DNA methylating andpyridyloxobutylating compounds.  DNAadducts formed include O6-methylguanine (O 6-meG) and O6-[4-oxo-4-(3-pyridyl)butyl]guanine        (O6-pobG).  O6-Alkylguanine-DNAalkyl-transferase (AGT) protects the cell by repairing O 6-alkylguanine. Epidemiological data suggest that genetic variation in AGT could be involvedin increased cancer risk.  Therefore, we investigatedif individuals with different AGT genotypes vary in their ability to repair O 6-pobG relative to O 6-meG.  Our data show that independent of AGTgenotype, human liver homogenates have similar abilities to repair O 6-pobG relative to O 6-meG in one sequencecontext.  Interestingly, O 6-pobG is not completelyrepaired even in the presence of excess levels of AGT.  Studies are under way to investigate themechanism behind incomplete O 6-pobGrepair.  [Supported by CA-115309].

Phenotyping human livers for repair of O6-methylguanine and O6-[4-oxo-4-(3-pyridyl)butyl]guanine adducts by O6-Alkylguanine-DNA alkyl-transferase

240th National Meeting (2010)

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