N-Nitrosobis(2-oxopropyl)amine (BOP) methylates hamster liver and pancreas DNA in vivo and also alkylates liver DNA with a longer chain of an, as yet, unknown nature. We are seeking to explain these qualitative and quantitative differences in alkylation using model chemical and in vitro systems of alkylation. Our earlier studies have identified four possible alpha-hydroxy derivatives of BOP and two of its nitrosamine metabolites which may result in methylation of pancreatic DNA. By studying the alkylation of DNA in isolated acinar, duct and islet cells using specifically radiolabeled BOP and its nitrosamine metabolites, we will be able to assess the relative contributions of each of the potential ultimate carcinogenic forms (alpha-hydroxynitrosamines) to the total alkylation observed following BOP administration. These data, combined with results obtained from determination of the persistence of O-methylguanine lesions in the DNA of these isolated cells following in vivo administration of BOP to hamsters, will give insight into the relative importance of the individual cell types in the initiation process and in establishing the precursors of the resulting malignant duct cells. Other proposed studies will further establish the validity of the chemical models (beta-oxidized nitrosocarbamates and alpha-acetoxy derivatives of beta-oxidized nitrosamines) for the proposed ultimate carcinogenic forms of beta-oxidized nitrosamines, the alpha-hydroxy derivatives.
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| Nagel, D L; Lewis, R; Fischer, M et al. (1987) Beta-oxidized N-nitrosoalkylcarbamates as models for DNA alkylation by N-nitrosobis(2-oxopropyl)amine in Syrian hamsters. IARC Sci Publ :71-4 |
| Nagel, D L; Mirvish, S S; Wallcave, L et al. (1987) Alpha-acetoxy derivatives of methyl-2-oxopropylnitrosamine: synthesis, hydrolysis rate and bacterial mutagenicity. Cancer Lett 36:325-32 |
