STUDIES ON THE MAMMARY CARCINOGENICITY OF HETEROCYCLIC ARYLAMINES IN COOKED MEAT

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To date three heterocyclic arylamines (HAAs) have been shown to be mammary carcinogens in rodent models: 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). We are currently examining the DNA adduction of HAA adducts in mammary epithelium, the distribution of radiolabeled HAAs to mammary tissue, and the excretion of HAAs and their metabolites into breast milk. Studies in lactating F344 rats indicate that IQ, MeIQx, and PhIP are distributed to the mammary gland. DNA adduction occurs in mammary gland with the level of adduction being highest for PhIP followed by IQ, and then MeIQx. All three compounds are excreted into breast milk. Suckling 5-day old pups show high levels of radioactivity derived from PhIP, IQ, or MeIQx in stomach, blood, kidney, and liver. Urine of pups is mutagenic in the Ames Salmonella mutagenicity assay. DNA adduct analysis of pups is being examined as a means of assessing the carcinogenic consequence of this route of exposure to the newborn. In addition, studies are underway in female Sprague-Dawley rats to examine and compare the induction of mammary tumors with PhIP and IQ, and their reactive metabolites, N-hydroxy-PhIP, and N-hydroxy-IQ, respectively. In future studies it is anticipated that tumors arising from these chemical treatments will be examined for mutations and/or amplifications in critical genes such as erb-B2, p53, c-myc, and c-HA-ras.