A variety of dietary factors have been implicated in the etiology of human cancers including exposure to carcinogenic substances present in foods. Highly mutagenic heterocyclic amines have been detected in cooked meats and these have been shown to produce tumors in rodents and in nonhuman primates. Both Phase 1 and 2 metabolism have been strongly implicated in the mutagenic activation of these heterocyclic amines and presumably are associated with carcinogenesis in vivo. Of the cooked meat-derived heterocyclic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) has been detected at the highest levels in most meats. Genotoxic activity of PhlP in bacterial and mammalian cellular assays, as well as tumorigenesis in rodent tumor bioassays, significantly differs from that of other food-derived heterocyclic amines which may suggest differential mechanisms of activation. The goals of the proposed studies are to evaluate metabolism of PhlP and other heterocyclic amines and to determine the mechanisms of activation of these compounds. Metabolism and activation of PhlP will be studied in rodent and human tissue preparations, in mammalian cells and in whole animals. DNA adduct formation in various tissues will be compared with metabolic capacity of these tissues. The effects of alterations in metabolic activation pathways on DNA adduct formation and on other genotoxic endpoints will be assessed. Mechanisms underlying differential potency of heterocyclic amines in bacterial and mammalian genotoxicity assays will be determined by using CHO cell lines expressing various levels of P450s and conjugation enzymes. DNA and protein adducts will be characterized for potential use along with PhlP metabolites as biochemical markers of exposure. In vitro metabolism of newly characterized heterocyclic amines will be assessed. These studies should provide information on target tissue specificity of PhlP and other heterocyclic amines and should provide useful data for extrapolation of risk to humans.
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