The overall objectives of the proposed work are to determine the metabolism and bioavailability of the mutagen MeIQx, as it occurs in the crust of fried beef. In order to characterize bioavailability of this substance we plan to specify routes of metabolic activation and deactivation, and macromolecular binding, in vitro and in vivo. In addition, absorption, excretion and tissue disposition of MeIQx and its metabolites will be determined. The proposed work is a collaborative effort which combines studies in synthetic chemistry and in metabolism. The specific objectives of the synthetic work are: 1) synthesis of MeIQx and [C14] MeIQx, 2) synthesis of [14C] N-OH-MeIQx, 3) preparation of a MeIQx-nucleotide adduct, and 4) synthesis of likely detoxification products of MeIQx. The objectives of the metabolism studies are: 1) identification of activated and deactivated metabolites of MeIQx, in vitro, and 2) absorption, distribution, excretion, and macromolecular binding in vivo, of MeIQx incorporated in beef crust. MeIQx is the most prevelent of the heterocyclic mutagens and carcinogens which occur in fried meat. A unique feature of these substances is their localization in the crust of fried meat. This characteristic may affect the extent to which the compounds are absorbed in the gastronintestinal tract and consequently the toxic effects of the substances. An understanding of the effects of meat on the biochemical characteristics of the mutagen is rquired for efforts to extrapolate results with animals to estimates of human risk.
