Unsymmetric dialkylnitrosamines such as methyl-n-amylnitrosamine (MNAN) induced esophageal cancer in rats. Our hypothesis, based on studies in the pancreas and bladder, is that nitrosamines such as MNAN are converted in the esophagus to active metabolites still bearing the nitrosamine group, e.g., Beta-oxo-alkyl derivatives, which are readily Alpha-hydroxylated to give alkylating agents. Supporting this view, MNAN was converted in vitro by rat esophagus into nitrosamine metabolites that contained hydroxy or keto groups. We propose the following studies: (1) We will identify and study MNAN metabolites produced in vitro by the esophagus and liver of rats and other species. (2) Esophageal metabolism of other nitrosamines will be compared. (3) The ability of rat and human esophageal organ cultures to form metabolites from MNAN and other nitrosamines will be compared. (4) The alkaline elution assay will be used to measure effects of MNAN, its metabolites, and other nitrosamines on esophageal DNA integrity. (5) We will study the alkylated DNA bases in rat esophagi produced from tritium-labeled MNAN, methyl-n-propylnitrosamine, and their active metabolites. (6) The diffusion rate into rat esophagus of MNAN, dimethylnitrosamine and the cocarcinogen catechol will be compared. (7) The mutagenicity of nitrosamine metabolites will be compared with that of the parent compounds. (8) We will examine the carcinogenicity of MNAN, 2-oxo-MNAN, 2-hydroxy-MNAN and 2-oxo-diethylnitrosamine in rats, and of MNAN in hamsters.
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