METABOLIC PROCESSING AND DNA ADDUCTION OF HETEROCYCLIC ARYLAMINE FOOD MUTAGENS

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Heterocyclic amines (HAA) comprise a group of compounds found in cooked proteinaceous foods, including beef, fish, chicken and pork. Three HAAs, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8- dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), have been shown to be potent mutagens in the Ames Salmonella mutagenicity assay and carcinogens in rodent models. Metabolic processing of these compounds plays an important role in the formation of DNA adducts, a critical factor in the initiation of carcinogenesis. Using recombinant cytochrome P-450s, we found that P-450IA2 is the predominant isozyme responsible for the N-hydroxylation of HAAs, and that N-hydroxylamines are reactive with DNA in vitro, both directly and following further activation via esterification. Our studies using rat liver indicate that phase II metabolism of the N-hydroxylamines by sulfotransferase and acetyl- transferase further activate these compounds. IQ has been shown to be a liver carcinogen in the nonhuman primates, while studies with MeIQx and PhIP are ongoing. Both DNA adducts of IQ and PhIP have been found in tissues of nonhuman primates. Adducts of MeIQx, however, are very low in these animals. N-Hydroxy-N-glucuronyl-IQ and N-hydroxy-N-glucuronyl-PhIP have been found in the urine of nonhuman primates fed IQ and PhIP, respectively, indicating that activation of these compounds via N-hydroxylation occurs in vivo. We have found that for all three compounds the pathways for detoxification include conjugation with sulfate and glucuronides. N-Demethylation is also a predominant pathway for detoxification of IQ in nonhuman primates. With PhIP, 4'- hydroxylation followed by sulfation is a predominant pathway for detoxification. To supplement the in vivo studies, phase I and II pathways of activation and detoxification of IQ, MeIQx, and PhIP are being examined in vitro in isolated tissue fractions from target and non- target organs of nonhuman primates and rodents using Ames Salmonella mutagenicity testing, HPLC, and 32-P-postlabling analysis.