Metabolism of the Food-Derived Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine by Lactating Fischer 344 Rats and Their Nursing Pups

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Abstract
An important class of dietary mutagens and carcinogens are the heterocyclic arylamine compounds that have been identified in a variety of cooked, protein-containing foods. Among these heterocyclic amines, 2-amino-l-methyl-6-phenylimidazo[4,5- l ]-pyridine (PhIP) is potentially the most important carcinogen for human cancer risk. We have recently observed that PhlP-derived radioactivity is excreted into the breast milk of lactating rats administered [ 3 H]PhIP. To better assess the significance of breast milk as a route of exposure of the newborn to dietary heterocyclic amines, we examined the metabolites of PhIP in breast milk and in urine of nursing pups. Lactating Fischer 344 rats with 5-day-old pups were given single oral dose of 10 mg/kg of [ 3 H]PhIP. We collected milk from the dams and urine from the pups and then analyzed the samples for metabolites of PhIP, using high-pressure liquid chromatography HPLC). PhlP-DNA adduct levels in the tissues of the pups were determined by 32 P-postlabeling analysis. Three radioactive peaks were observed by HPLC separation of milk samples: an unidentified early eluting peak, 4′- hydroxy-PhlP, and PhIP. Four metabolites and the parent compound were found in urine of the pups nursed by dams given radiolabeled PhIP: PhlP- 4′-O-glucuronide, PhIP-4′-sulfate, 4′- hydroxy-PhlP, and N 3 -hydroxy-PhIPNJ- glucuronide. 4′-Hydroxy-PhIP and its conjugates contributed approximately 60% of the radioactivity found in the urine. By 32P-postlabeling analysis, PhlP-DNA adducts were detected in spleen, lung, heart, kidney, liver, and stomach of pups at mean levels ranging from 0.06 to 0.55 adducts/107 nucleotides. The large percentage of 4′-hydroxy-PhIP and its conjugates in the urine indicates that 5-day-old pups detoxify PhIP and further metabolize 4′-hydroxy-PhIP obtained from the breast milk. The presence of the glucuronide conjugate of N-hydroxy - PhlP in the urine of pups and the lack of detectible conjugate or Nhydroxylamine itself in breast milk suggest that PhIP from breast milk undergoes metabolic activation via N-hydroxylation in 5-day-old rat pups. This conclusion was further supported by the observation that hepatic S9 fractions from the pups activated PhIP to a mutagen in the Ames Salmonella mutagenicity assay and by the presence of PhlP-DNA adducts in the tissues of the pups. The findings reported here may have carcinogenic and toxicologic implications for the offspring of women who breast-feed and consume a diet rich in cooked meat. [J Natl Cancer 86:1065-1070,1994]

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