METABOLIC ACTIVATION OF ARYLAMINES IN LEUKOCYTES

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The objective of this research program is to elucidate the processes by which leukocytes cause the bioactivation or toxification of arylamines and related chemicals. Research will emphasize the ability of the various types of leukocytes to cause arylamines and aromatic hydroxamic acids to bind covalently with cellular macromolecules, a process which can lead to the disruption of normal cell function and cause cell death. The macromolecules of greatest interest are DNA and RNA. Covalent binding to these nucleic acids will be studied both within the leukocytes which are responsible for causing such binding, and also to nucleic acids outside the activating cells. The covalent binding of arylamines and hydroxamic acids to the macromolecules of cells that are not involved in the metabolic activation of such chemicals would indicate an important mechanism by which leukocytes can damage neighboring cells. The potential for phagocytic leukocytes (granulocytes, monocytes and macrophages) to cause damage to surrounding cells is already known to result from the release of reactive oxygen species following the normal "respiratory burst" of such cells. The presence of xenobiotics, which are themselves susceptible to oxidation by these leukocyte products, could readily alter the nature of damage caused by these phagocytic cells. The reactive metabolites produced by leukocyte oxidation of arylamines and hydroxamic acids are known to bind to nucleic acids; therefore, the potential for genotoxic effects is of major concern. The emphasis on arylamines is because of the importance of this class of chemicals as a source for pharmaceuticals, pesticides and other environmental chemicals. The interest in hydroxamic acids arises from the fact that they are known to be arylamine metabolites that are produced primarily in the liver, and which are responsible in part for the genotoxic and necrotic properties of arylamines. Hydroxiamic acids are thought to be latentiated forms of metabolic activation products that can be transported to tissues throughout the body after being produced in the liver. Further transformation of hydroxamic acids is necessary for their potential toxicity to be released. Certain leukocytes are able to cause the final bioactivation of hydroxamic acids by mechanisms that will be studied in this program. A knowledge of the processes by which leukocytes cause the toxification of arylamines and hydroxamic acids will enable scientists to devise measures to minimize or prevent the adverse effects of such toxification reactions on human health.