Arylamine chemicals are a significant cause of occupation and environment-related cancer in humans. Arylamines are used as intermediates in the synthesis of numerous organic compounds, as antioxidants in a host of consumer products, and are released as pyrolysis products in the combustion of protein and organic matter. Critical risk determinants in the development of chemical carcinogenesis from arylamines include predisposing host factors in addition to exposure. Recent human epidemiological studies strongly suggest a genetic predisposition to arylamine-induced bladder cancer, and to the more invasive forms of bladder cancer, among slow acetylators. Slow acetylation capacity is controlled by two codominant alleles at a single locus. Over one-half of all Black and Caucasian Americans are slow acetylators. Various acetyl transfer steps have been identified in the metabolic activation and deactivation of arylamines to their ultimate carcinogenic forms, including acetyl coenzyme. A (AcCoA)-dependent intermolecular N-acetylation of arylamines, O-acetylation of N-hydroxy-arylamines, AcCoA-independent intramolecular N,O-acetyltransfer of arylhydroxamic acids, and deacetylation of arylamides and arylhydroxamic acids. Preliminary data suggest that the enzymatic capacity for N-and O-acetylation capacity are controlled at a single and common genetic locus and that they are catalyzed by common acetyltransferase isozymes. To test this hypothesis, we propose to construct Bio. 82.73/H/Natr and Bio. 1.5/Natr congenic inbred hamster strains. Through comparisons between these homozygous rapid acetylator congenic strains and their corresponding homozygous slow acetylator background strains, we will make a direct assessment of the role of the polymorphic N-acetylator gene locus on various hepatic and extrahepatic acetyltransferase isozymes that catalyze the acetylation and/or deacetylation of carcinogenic arylamines, and their corresponding arylamides, arylhydroxylamines and arylhydroxamic acids. Companion characterizations also will be carried out with acetylation isozymes derived from human organ donors.
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