METABOLIC ACTIVATION OF ARYLAMINES IN LEUKOCYTES

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The purpose of this program is to elucidate certain biochemical processes that are partially responsible for the genotoxicity of arylamines and nitroso aromatic compounds. The arylamines constitute some of our most important chemicals. Arylamines and derivatives are common pharmaceutical agents and the extensive use of arylamine derivatives as pesticides in modern agricultural practice continues to increase. On the other hand, a knowledge of the biological fate and effects of arylamines in living organisms is very incomplete. Since many arylamines and related chemicals are known carcinogens, it is necessary that a detailed knowledge of the metabolism of these chemicals in higher animals be attained. This program will study the extent to which model aromatic amines are metabolized to hydroxamic acids, since hydroxamic acids are known to account for much of the toxicity of aromatic amines. The program will examine the biochemical processes that convert nitroso aromatic compounds to hydroxamic acids possessing unusual N-acyl groups. The specific biochemical pathways responsible for such hydroxamic acids arise from the interaction of a nitroso aromatic compound with a thiamin-dependent enzyme. Another facile, but non-enzymatic reaction that causes the production of the N-formyl type hydroxamic acid under physiological conditions is the reaction a nitroso aromatic with glyoxylic acid. The bioactivation reactions of interest will be studied by employing leukocytes, since these blood cells comprise sizable and highly disseminated tissues. Total and purified leukocyte types (neutrophils, monocytes, macrophages, lymphocytes) will be obtained from New Zealand white rabbits, Syrian golden hamsters, Sprague Dawley rats and banked human blood. The results of this program will provide valuable data to help design measures to minimize mankind's exposure to, or damage from, potentially genotoxic chemicals.