Trichloroacetate (TCA) and dichloroacetate (DCA) are produced from the treatment of drinking water with chlorine. They are also formed in the gastrointestinal tract in animals administered aqueous solutions of chlorine. As important metabolites of halogenated ethane and ethene solvents they are potentially involved in the induction of liver tumor in mice. DCA and TCA induce the synthesis of hepatic peroxisomes and induce liver tumors in B6C3F1 mice. DCA is the more potent compound in both instances. We propose to examine mechanisms by which DCA and TCA are able to act as carcinogens. In our laboratory we have found that DCA and TCA are capable of inducing single strand breaks (SSB) in hepatic DNA following in vivo administration. Again DCA is much more potent in this regard than is TCA. This proposal directs itself towards three problems; 1.) the extent to which DCA and TCA are produced on consumption of chlorine and their metabolism once absorbed, 2.) the mechanism by which DCA and TCA induce peroxisome proliferation and 3) The mechanism by which they induce SSB in DNA. In pursuit of questions 2 and 3 the important questions are whether SSB produced by these compounds is dependent upon peroxisomes, is the response exacerbated by peroxisome proliferation or do they arise independently. The literature reports that DCA can be converted to glyoxylate in vitro, although the extent this occurs in vivo has never been documented. Production of significant quantities of this metabolite in vivo could be the basis of a redox cycle operating between glycolate oxidase in peroxisomes and lactic dehydrogenase in the cytosol with net synthesis of hydrogen peroxide. Hydrogen peroxide and the resulting hydroxyl radical could be responsible for the SSB in DNA. The demonstration of this cycle and documentation of the formation of hydrogen peroxide will be conducted in primary hepatocytes whereas metabolic experiments are to be conducted in intact animals. The relative time course of the induction of SSB in DNA and peroxisome synthesis will be examined both in vivo and in vitro.
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