Naturally occurring and synthetic isothiocyanates are effective inhibitors of chemical carcinogenesis by a variety of carcinogens including polynuclear aromatic hydrocarbons and aromatic amines. However, only limited information is available on their ability to inhibit cancer induction by nitrosamines. This represents a significant gap in our knowledge of chemoprevention because nitrosamines are an environmentally prevalent class of powerful carcinogens. Our preliminary data have clearly demonstrated that isothiocyanates can inhibit the metabolic activation and DNA binding of nitrosamines. These results and those of other investigators strongly indicate that isothiocyanates will be effective inhibitors of nitrosamine carcinogenesis. The four programs of this project will focus on the effects of isothiocyanates on the metabolic activation and carcinogenicity of three important nitrosamines: 4-(methylnitrosamino)-1- (3-pyridy1)-1-butanone (NNK), N-nitrosodimethylamine (NDMA), and N- nitroso(4-hydroxybuty1) butylamine (BHBN). Program 1, """"""""Isothiocyanates: Structure-activity Relationships for Inhibition"""""""" will use assays for inhibition of DNA adduct formation from NDMA, NNK, and BHBN to probe the structural requirements favoring inhibition by isothiocyanates of nitrosamine metabolic activation. Program 2, """"""""Isothiocyanates; Toxicity and Activity in Human Tissues"""""""" will focus on the potential toxic effects of the isothiocyanates and on their ability to inhibit the metabolic activation of nitrosamines in human tissue. Program 3, """"""""Mechanisms of Inhibition of Nitrosamine Bioactivation by Isothiocyanates"""""""" will determine the effects of isothiocyanates on enzymes involved in the metabolic activation of nitrosamines, in particular the cytochrome p-450 system. Program 4, """"""""Chemoprevention of Nitrosamine Carcinogenesis by Isothiocyanates"""""""" will examine the effectiveness of the isothiocyanates as inhibitors of tumor induction by NNK, NDMA, and BHBN. These four highly focused programs will provide essential information on the chemoprevention of nitrosamine carcinogenesis by isothiocyanates.
