The mechanism of tumor induction by unsymmetric nitrosamines is poorly understood. Alpha-hydroxylation activates these carcinogens to DNA alkylating agents by generating a metabolite that decomposes to an aldehyde and a diazohydroxide. The diazohydroxide, presumably via a diazonium ion, alkylates DNA. Unsymmetric nitrosamines have two alpha- hydroxylation pathways that lead to two different types of DNA adducts. Interactions between these two pathways likely contribute to the carcinogenic activity of the nitrosamine. Our studies indicate that there are interactions between the two activation pathways of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)- 1 butanone (NNK). This tobacco-specific nitrosamine selectively induces lung tumors in laboratory animals and is a possible human carcinogen. NNK is activated to either a methylating agent or a pyridyloxobutylating agent. Experimental data support a carcinogenic mechanism for this compound in which the formation of O/6-methylguanine (O/6-mG) is important for the initiation of tumorigenesis in target tissues. Pyridyloxobutylating compounds, such as 4-(acetoxymethylnitrosamino)-1-(3- pyridyl)-1-butanone (NNKOAc), can enhance the lung tumorigenic activity of methylating agents in A/J mice by increasing the levels of O/6-mG in lung DNA. Interestingly, pyridyloxobutyl DNA adducts are capable of interfering with the ability of O/6-alkylguanine-DNA alkyltransferase (AGT) to repair O/6-mG in vitro. Our hypothesis is that the pyridyloxobutyl DNA adducts generated from NNK contribute to the lung tumorigenic activity of NNK in the A/J mouse by interfering with O/6-mG repair by AGT in vivo. To test this hypothesis, we will: 1) determine the relative level of AGT reactive pyridyloxobutyl DNA adducts to O/6-mG in lung DNA isolated from NNK-treated A/J mice; 2) investigate the involvement of AGT in the repair of pyridyloxobutyl DNA adducts in vivo; 3) use an in vitro system to determine whether these adduct levels are sufficient to affect the repair of O/6-mG; 4) elucidate the mechanism by which pyridyloxobutyl DNA adducts interact with AGT. The results of our studies will lead to a better understanding of mechanisms of lung cancer induction by NNK. In addition, this mechanism is likely applicable to other unsymmetric nitrosamines as well as carcinogenic mixtures such as tobacco smoke, a known human carcinogen.
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