METABOLIC PROCESSING AND DNA ADDUCTION OF HETEROCYCLIC ARYLAMINE FOOD MUTAGENS

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The food-derived heterocyclic arylamines (HAAs) are produced in meats during the process of cooking. To date, 19 HAAs have been identified (partially identified) in various cooked meats. Many of these compounds are potent mutagens in the Ames Salmonella assay and 10 HAAs have been shown to be carcinogenic in rats and/or mice. We also showed that 2- amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus monkeys. Our studies have shown that these compounds are procarcinogens that require metabolic activation for genotoxicity. Thus, the metabolic processing of these compounds is a critical feature with respect to their carcinogenicity. Studies examining the phase II activation of N-hydroxylamines of IQ, 2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) showed that four pathways may contribute to the activation of these compounds: O-acetyltransferase, sulfotransferase, t-RNA synthetase, and phosphatase. The amount of metabolism was determined by the tissue, the species, and the substrate. Studies on the characterization of DNA adducts of HAAs showed that the N-acetoxy derivatives of IQ, MeIQx, and PhIP form three major adducts with the guanine base. The major adduct of each of these compounds was synthesized and identified as the C8-guanine adduct, indicating a similarity among these compounds in DNA adducts formed. The major adducts were identified in our P-postlabeling profiles. Studies with PhIP show that cynomolgus monkeys possess a good capacity to metabolically activate this compound in vivo and that this activation results in DNA adduction that can be found in all tissues examined to date, including white blood cells. The major pathway of activation was identified as N-hydroxylation. The major pathway of detoxification was identified as 4'-hydroxylation followed by conjugation with sulfate.