Arylamine and hydrazine drugs and carcinogens frequently require metabolic activation to produce carcinogenesis and/or necrosis in various tissues. Individual susceptibility to these toxicities are often due to genetically determined differences in the metabolic enzymes catalyzing activation and/or deactivation pathways. This proposal seeks to identify genetic variation in some important pathways utilizing a genetically-defined inbred animal model. Recently, we identified inbred Syrian hamster strains that exhibit very large differences in acetylation capacity. This finding is particularly pertinent to the overall objectives of this proposal because this enzyme is of major importance in two acetyl transfer steps in arylamine-induced carcinogenesis and hydrazine-induced liver necrosis. These acetyl transfer steps can represent either activation or deactivation pathways dependent upon the tissue and the sequence. Genetic differences in acetylation capacity have particular clinical interest because human epidemiological findings suggest that arylamine-induced bladder carcinogenesis and hydrazine-induced liver necrosis susceptibility correlate with acetylator status. This proposal outlines a characterization of the inbred hamster model with respect to genetic variation in N,O-arylhydroxamic acid acyltransferase, sulfotransferase and deacetylase, in addition to N-acetyltransferase. An emphasis of the proposal focuses on further characterization of N-acetylation differences in liver and in key extrahepatic tissues that are target organs for arylamine and hydrazine-induced toxicity. Genetic differences in N-acetyltransferase activity will also be investigated in whole blood or certain blood cells to develop conditions applicable to humans. Identification of a procedure to distinguish rapid and slow acetylator humans from a small sample of blood has remained elusive, compromising many epidemiological studies that attempt to correlate chemical-induced carcinogenesis or necrosis with acetylator phenotype, producing inconsistent and controversial results. Since the inbred hamster model exhibits such large differences in N-acetylation capacity, it serves as a promising model for these studies.
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NIH ExPorter