N-Nitrosamines are a group of carcinogens which occur widely in the environment, food, beverages, and tobacco products, and can also be produced endogenously. Metabolic activation is an essential step for these compounds to exert their toxic and carcinogenic actions. It is also a key factor in determining the remarkable organ specificity and species variability of their carcinogenic actions. We have made substantial progress in elucidating the enzymatic basis for the activation of nitrosamines. We plan to continue this successful line of research and to pursue in-depth studies using the following approaches: 1. To elucidate the mechanisms of activation and possible detoxification pathways of N-nitrosodimethylamine and other nitrosamines by studying (a) detailed kinetic parameters, (b) role of cytochrome b5, (c) structure-reactivity relationship, (d) kinetic isotope effect, (e) role of cell integrity, and (f) involvement of oxygen radicals. 2. To study the metabolism of selected nitrosamines by different types of microsomes, purified cytochrome P-450 isozymes, and isolated cells.
The aim i s to understand the molecular basis for the tissue and species variabiltiy, as well as the modulation, of nitrosamine metabolism. 3. To study the metabolism of nitrosamines by human tissue samples and to understand the enzymatic basis for the metabolism. 4. To delineate the relationship between the metabolism of nitrosamines and their activation to mutagens for V79 cells as well as to examine the genotoxic damage involved. The studies will yield precise information on the enzyme specificity and mechanisms of the activation of nitrosamines. Such information is important to the understanding of nitrosamine carcinogenesis in animals and humans. This knowledge will be useful in designing potential means for cancer prevention.
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