The long term goal of this research is to understand fundamental and applied aspects of the chemistry of carcinogenic nitrosamines. Nitrosamines are a large class of compounds of varied structure to which there is human exposure through endogenous formation and environmental sources. Most of the nitrosamines investigated are carcinogenic or mutagenic in the Ames test when activated by liver microsomes. Nitrosamines are found in groundwater, foods, personal care products, and tobacco products and are encountered in a number of industrial environs, in particular in rubber manufacturing and curing facilities, metal and leather working concerns. The mechanism by which the simplest nitrosamines manifest their deleterious actions is reasonably well understood. They tend to target the oxygen atoms of DNA. By means of the adducts they form they cause replicative polymerases to mis-insert opposite these lesions leading to mutation. Some fundamental aspects are not well understood - for example why the diazonium ions formed from nitrosamines tend to target the oxygen atoms and why there are mutation/adduct deposition hotspots. This proposal contains experimental approaches by which these issues can finally be resolved. The proposal also seeks to understand the more complex chemistry of a """"""""non-simple"""""""" nitrosamine - N- Nitrosomorpholine (NMOR) - to which there is human exposure. Recent work from this laboratory has demonstrated that a metabolite of NMOR decomposes to give nucleoside adducts of novel structure, ones that contain a pendant aldehyde. These slowly decompose to hydroxyethyl lesions. Such pendant aldehyde adducts are likely widely encountered from sources such as other nitrosamines and the products of DNA oxidation and lipid peroxidation as well as other environmental toxicants. It is intended to understand the damage spectrum derived from the metabolite, how it evolves with time and also to construct the novel adducts in oligonucleotides and to study their structure and cross-linking activities by NMR and trapping studies. The combination of novel technical and synthetic approaches are integrated toward a complete and detailed understanding of fundamental aspects of DNA damage and structures that have broad application. ? ? ?
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