Certain hydroxamic acids with the structure of ArCONHOH or RCONHOH are mutagenic for bacteria and mammalian cells, and teratogenic in experimental animals, and must, therefore, be regarded as potential environmental hazards. Yet, little is known in regard to the biotransformation of these compounds to reactive species. Our previous results showed that 2-NHA is a strong direct mutagen for S. typhimurium TA98 and that O-acetylation increased its mutagenicity. Results from the experiments conducted in the initial granting period have demonstrated that 2NHA-OAc underwent Lossen rearrangement at 37 degree, pH 7; the mutagenicity of 2-NHA is not dependent on its acetylatyion to an O-acetate; that these compounds can be activated independently to form DNA adducts in bacteria; H202 mediated peroxidation can activate these mutagens in a cell-free system and form adducts with nucleic acids. Therefore, it is hypothesized that 1) hydroxamic acids and their O-acetates are potential environmental genotoxins for humans because of their activation by oxidative enzymes, and 2) the activation mechanisms of hydroxamic acids may involve peroxidation and that of the O-acetates may involve the lossen rearrangement and peroxidation. Our experimental approaches are: A. Carry our the Ames test using S. typhimurium TA98 in the presence of mammalian peroxidative enzymes to determine the effects of peroxidation on the mutagenicies of these compounds. B. Reaction of these compounds with the DNA of tissue slices of ram seminal vesicle, which is rich in prostaglandin H synthase activity, and rat liver, which has little of this peroxidase activity, to assess the importance of the peroxidative reactions. C. To investigate the peroxidative metabolic activation by bacterial enzymes by use of the Ames test and added H202, as well an nucleic acid binding assays using bacterial enzyme preparations. D. DNA adducts produced from 2-NHA and its O-acetate in Salmonella, in ram seminal vesicle and rat liver, and form reactions with DNA with or without enzyme-mediation, will be identified. Results obtained from these studies will aid in the elucidation of activation mechanisms of this class of compounds.
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