Halonitriles, which are shown to be mutagenic and carcinogenic, have been detected in chlorinated drinking water supplies as water disinfectant byproducts. Previous studies in our laboratory have indicated that acrylonitrile (VCN) and haloacetonitriles (HAN) injure the gastrointestinal (GI) tract and this adverse effect is modulated by sulfhydryl reagents. In addition, our studies indicate extensive uptake and accumulation of the parent compounds or its metabolites within GI tissues. The long-term objective of this study is to investigate the genetic and epigenetic mechanisms of carcinogenic and pathogenic potential of these compounds at their target site of action, the GI tract, and to characterize the molecular sites of interactions of VCN and HAN which lead to the GI toxicity and/or cancer. Specifically, we plan to study: a) the direct interactions of VCN, HAN, and their metabolites with DNA proteins in GI tissues in vivo and in vitro; b) the effect of glutathione and glutathione transferases (GSHT) modulation on the extent and types of these direct molecular interactions; c) the effect of VCN and HAN on the rate and magnitude of DNA and protein turnover in GI tissues; and d) the role of the GI microsomal and cytosolic enzymes in the activation and deactivation of aliphatic nitriles (extrahepatic metabolism), using molecular interactions, metabolism and toxicity as markers. The significance of the proposed research is not restricted to elucidation of the molecular mechanisms of gastrointestinal damage induced by the mentioned nitriles. The study of simple molecules such as these will aid in developing models to examine the mechanisms of chemically-induced GI neoplastic transformations in man.
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