Distribution and metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) in female rats and their pups at dietary doses

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammarycarcinogen in female rats and is present in a wide variety of cooked meats.We address here the excretion of PhIP and its metabolites into thebreast-milk of lactating rats and the ability of chlorophyllin, a foodproduct derivative with chemopreventive properties, to affect these levelsat low PhIP doses. Lactating female F344 rats with suckling pups wereorally administered 50, 500 and 1000 ng [14C]PhIP/kg body weight. Theexcretion of the [14C]PhIP into milk and its distribution among the mammarytissue, liver and blood of the dam, as well as among stomach contents andliver of their suckling pups was measured using accelerator massspectrometry (AMS). PhIP, PhIP-4'- sulfate, 4'-hydroxy-PhIP, andN2-hydroxy-PhIP-N3-glucuronide were found in the milk at all doses. Thechlorophyllin (500 microg/kg) co- administration with PhIP (500 ng/kg)caused increased levels of [14C]PhIP in the milk (32%) and stomach contents(35%) of the pups relative to the animals not receiving chlorophyllin atthese low PhIP doses. In contrast, lower [14C]PhIP levels in thechlorophyllin treated animals were observed in the blood (47%) and mammarytissue (68%) of the dam, as well as the pup's liver tissue (37%) comparedto the animals receiving only PhIP. Chlorophyllin co-administrationresulted in an increased amount of N2-hydroxy-PhIP-N3-glucuronide (42%),increased PhIP (79%) and decreased levels of PhIP-4'-sulphate (77%)relative to the animals not receiving chlorophyllin. These results suggestthat PhIP and PhIP metabolites are present in the breast-milk of lactatingrats at human dietary PhIP exposures and that PhIP is absorbed by thenewborn. Furthermore, these results suggest that other dietary componentscan affect the dosimetry of PhIP in breast-feeding offspring.