This application for an Outstanding Investigator Grant, by Dr. Stephen S. Hecht seeks support for a program of research on """"""""Metabolic Activation of Carcinogens,"""""""" now in its sixth year. The goal of the program is to understand the mechanisms by which environmentally prevalent nitrosamines and polynuclear aromatic hydrocarbons (PAHs) initiate the carcinogenic process. Specifically, the goals are to determine pathways of carcinogen activation and detoxification, to elucidate the structures of DNA adducts formed in the activation process, to determine the significance of these adducts in the carcinogenic process, to understand structure-carcinogenicity relationships, and to develop methods to detect relevant metabolites, protein adducts, or DNA adducts in humans. Proposed research will focus on tobacco-specific nitrosamines (TSNs), dietary and endogenously formed cyclicnitrosamines, and ubiquitous PAHs. Previously unexplored aspects of metabolic activation/ detoxification pathways will be explored, and the importance of stereochemical features evaluated. Technical approaches will include a unique combination of organic synthesis, structure assessment, analytic organic chemistry, in vivo and in vitro metabolic studies, molecular biological analyses, and carcinogenicity assays. The proposed studies are based on findings made during the previous period of support.
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