BIOALKYLATION IN CHEMICAL CARCINOGENESIS

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The objectives of this biochemical research are 1) to critically test the structure-activity relationship theory developed in this laboratory over the past 20 years, 2) to increase our understanding of the nature of the reactions that are involved in the metabolic activation of polynuclear aromatic hydrocarbons, and 3) to understand the reasons for the striking structure-activity relationships in this class of compounds. The metabolism of a series of closely related hydrocarbons will be investigated and compared, using HPLC, GC/MS, and 32P postlabelling and a number of reference compounds, and their activation to electrophilic intermediates that react with nucleic acids will be studied, in vitro and in vivo, in rat liver, lung, and subcutaneous tissue. We expect to be able to distinguish between the reactions of the hydrocarbons leading to carcinogenesis and the reactions leading to inactivation. The long term objectives of these studies are 1) to correctly predict the carcinogenicity of a polynuclear aromatic hydrocarbon from a knowledge of its features of structure and metabolism, and 2) to assess, in metabolism studies, the susceptibility of subcutaneous tissue, in comparison with lung and liver, to carcinogenesis by polynuclear aromatic hydrocarbons. A more complete understanding of the most important structural features and reactions involved in polynuclear aromatic hydrocarbon carcinogenesis may eventually lead to methods for the prevention of some of the human cancer that is currently considered to be caused by this class of chemical carcinogens.