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 mammary carcinogen in female rats and is present in a wide variety of cooked meats. We address here the excretion of PhIP and its metabolites into the breast-milk of lactating rats and the ability of chlorophyllin, a food product derivative with chemopreventive properties, to affect these levels at low PhIP doses. Lactating female F344 rats with suckling pups were orally administered 50, 500 and 1000 ng [14C]PhIP/kg body weight. The excretion of the [14C]PhIP into milk and its distribution among the mammary tissue, liver and blood of the dam, as well as among stomach contents and liver of their suckling pups was measured using accelerator mass spectrometry (AMS). PhIP, PhIP-4'-sulfate, 4'-hydroxy-PhIP, and N2-hydroxy-PhIP-N3-glucuronide were found in the milk at all doses. The chlorophyllin (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 at these low PhIP doses. In contrast, lower [14C]PhIP levels in the chlorophyllin treated animals were observed in the blood (47%) and mammary tissue (68%) of the dam, as well as the pup's liver tissue (37%) compared to the animals receiving only PhIP. Chlorophyllin co-administration resulted 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 suggest that PhIP and PhIP metabolites are present in the breast-milk of lactating rats at human dietary PhIP exposures and that PhIP is absorbed by the newborn. Furthermore, these results suggest that other dietary components can affect the dosimetry of PhIP in breast-feeding offspring.
Mauthe
R J
RJ
Molecular and Structural Biology Division and Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94551, USA.
Snyderwine
E G
EG
Ghoshal
A
A
Freeman
S P
SP
Turteltaub
K W
KW
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002735:Chlorophyllides / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007774:Lactation; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D002273:Carcinogens; D002735:Chlorophyllides; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C007020:chlorophyllin