Uptake of the colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by different segments of the rat gastrointestinal tract: its implication in colorectal carcinogenesis.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a colon carcinogen in rats. In the present study the absorption of PhIP in the small and large intestine of Fischer 344 rats was determined, and the relevance of the differences in the degree of absorption of PhIP along the gastrointestinal axis for the PhIP-mediated colon carcinogenesis process is discussed. PhIP uptake was low in the different gut sections of Fischer 344 rats, the PhIP tissue levels varying in the following order: proximal jejunum>distal jejunum>proximal colon>distal colon=rectum. Furthermore, abcc2 was mainly expressed in the proximal parts of the small intestine, in particular in the proximal jejunum. Extremely low expression levels were observed in distal jejunum, ileum, caecum and proximal colon, whereas abcc2 was almost not detected in distal colon and rectum. These data, together with previously published results, lend support to the hypothesis that PhIP is taken up in the proximal segments of the small intestine and after being metabolically activated in the liver reaches the stem cell compartment of the colonic crypts via the blood circulation, the crypt cells in the distal colon and rectum being particularly at risk, since these almost do not express abcc2.
Nicken
Petra
P
Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany.
Hamscher
Gerd
G
Breves
Gerhard
G
Steinberg
Pablo
P
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002273:Carcinogens; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine