Although toxicity of chloromethanes and chloroethanes has been extensively studied, toxicity of chloropropanes (CP) has not. The studies described here are proposed not only because the toxicology of this group of important industrial chemicals has not been considered, but also because their three-carbon structure suggests an interesting hypothesis on the biochemical interaction of CP and cell constituents. This hypothesis is that there is sufficient structural similarity between three-carbon metabolic intermediates and CP (or their biotransformation products) that the CP inhibit enzymes using these intermediates. The purpose studies is to investigate the plausibility of this hypothesis by characterizing the interaction between intermediary metabolic pathways and CP and their biotransformation products. In addition, the proposed studies will investigate the involvement of recognized mechanisms in CP hepatotoxicity. Specifically, the proposed studies will 1) measure effects of chloropropanes on pathways of intermediary metabolism occurring in liver cell fractions, and 2) measure CP-induced lipid peroxidation and covalent binding of CP biotransformation products to liver microsomal protein. The first objective will be pursued using cell fractions incubated with various CP. Cell fractions containing functioning enzymes of glycolysis, gluconeogenesis, the citric acid cycle, oxidative phosphorylation, and three-carbon amino acid synthesis will be monitored using measurements of substrate disappearance or product appearance. Pathways affected by CP will be studied in more detail through the use of various initiating substrates, measurements of intermediates' concentrations, and measurements of enzyme's activities. The second objective will be pursued using liver microsomes incubated with radiolabelled CP. Lipid peroxidation and covalent binding to microsomal protein due to selected CP will be measured. These studies will provide information on the interaction between intermediary metabolic pathways and CP, and suggest whether these interactions might be a basis for CP toxicity. In addition, the studies will indicate whether CP hepatotoxicity might be mediated by lipid peroxidation or covalent binding, thus implying similarity in mechanism between CP and the lower chloroalkanes.
