Genetic and environmental factors have been implicated in the etiology of cancers of the breast, colon, and prostate, but the identities and relationships between these factors are poorly understood. Bioassay studies in rodents show that aromatic and heterocyclic amine carcinogens produce tumors at each of these sites, and human epidemiological studies suggest that genetic polymorphisms in enzymes that metabolize aromatic and heterocyclic amines may predispose individuals to these cancers. This proposal is designed to further understand the role of genetic polymorphisms, particularly for acetyltransferases, in predisposition to cancers from aromatic and heterocyclic amine chemicals. The applicant proposes further studies in humans and the rapid and slow acetylator congenic hamster and inbred rat models developed and characterized over the previous project period to test the hypothesis that rapid acetylator genotype (NAT1 and/or NAT2) is a risk factor for cancers of the breast, colon, and prostate. Experiments are proposed to determine NAT1, NAT2, CYP1A1, GSTM1, and possibly CYP1A2 genotypes in population-based case-control cohorts of breast, colon, and prostate cancer subjects. Experiments are proposed to assess the role of NAT2 genotype on the incidence of breast, colon, and prostate tumors in rapid and slow acetylator congenic hamsters administered aromatic or heterocyclic amines. Various biomarkers such as DNA adducts, gene mutations, and aberrant crypts will be identified and compared. In order to better understand the role of NAT1 and NAT2 in the metabolic activation of N-hydroxy aromatic and heterocyclic amine carcinogens, experiments are proposed to determine the regiospecificity of recombinant human, mouse, rat and Syrian hamster acetyltransferases to catalyze N-, O-, and N,O-acetylation of aromatic and heterocyclic amines by construction, cloning, and recombinant expression of NAT1/NAT2 chimeric alleles.
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