It is estimated that 90% of all lung cancers are due to tobacco smoke, but only one out of nine smokers will be diagnosed with lung cancer. Metabolic activation of many carcinogens leads to the formation of reactive intermediates that react with DNA to form DNA adducts. These adducts can interfere with normal cell division, inducing cytotoxicity. If they persist, the DNA adducts may miscode during DNA replication, resulting in permanent mutations and, eventually cancer. We hypothesize that genetic variation in DNA damage repair and response genes pathways plays a significant role in the individual differences in the risk of developing tobacco-related cancers. To test this hypothesis, we are phenotyping International HapMap Epstein-Barr virus-transformed B-lymphocytes for their sensitivity to the cytotoxic and genotoxic properties to the reactive metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and correlating these sensitivities to the cell's ability to repair NNK-derived DNA adducts; NNK is a human carcinogen that induces lung specific tumor formation in laboratory animals. In this current study, commercially available N-nitroso-N-methylurethane (NMUr) was employed to model the DNA methylation pathway of NNK. Repair of the mutagenic and toxic DNA adduct, O6-methylguanine (O6-mG), was monitored by LC-MS/MS analysis. Preliminary results indicate that individual susceptibility to the cytotoxic effects of NMUr is determined by more than just rates of O6-mG repair [Supported by CA-138338].

Inter-individual differences in sensitivity to cytotoxic and genotoxic effects of a tobacco carcinogen

248th National Meeting (2014)

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