The colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is actively secreted in the distal colon of the rat: an integrated view on the role of PhIP transport and metabolism in PhIP-induced colon carcinogenesis

• Published in: Archives of toxicology Vol. 87; no. 5; pp. 895 - 904
• Main Authors: Nicken, Petra, Schröder, Bernd, von Keutz, Anne, Breves, Gerhard, Steinberg, Pablo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2013; Springer Nature B.V
• Subjects: Adenocarcinoma - chemically induced; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological Transport; Biomedical and Life Sciences; Biomedicine; Carcinogens; Carcinogens - pharmacokinetics; Carcinogens - toxicity; Colon - drug effects; Colon - metabolism; Colon - pathology; Colonic Neoplasms - chemically induced; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Enterocytes - drug effects; Enterocytes - metabolism; Enterocytes - pathology; Environmental Health; Genotoxicity and Carcinogenicity; Glycoproteins; Imidazoles - pharmacokinetics; Imidazoles - toxicity; Jejunum - drug effects; Jejunum - metabolism; Jejunum - pathology; Male; Multidrug Resistance-Associated Proteins - metabolism; Occupational Medicine/Industrial Medicine; Pathogenesis; Pharmacology/Toxicology; Rats; Rats, Inbred F344; Toxicity; P-glycoprotein; Ussing chamber; PhIP transport; Colon cancer; Breast cancer resistance protein; Multidrug resistance protein 4
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-012-1006-0

Epidemiological studies show that a positive correlation exists between the consumption of strongly heated meat and fish and the development of colorectal tumours. In this context, it has been postulated that the uptake of toxic substances formed during meat and fish processing such as heterocyclic aromatic amines (HCAs) may be causally related to colon carcinogenesis. In a previous study, we have shown that 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP), the most abundantly formed HCA in the above-mentioned food items, is mainly absorbed in the small intestine (i.e. proximal jejunum) of the rat. In the present study, we analysed whether PhIP can actively be secreted by enterocytes in the rat proximal jejunum and distal colon. Unidirectional PhIP flux rates from the mucosal-to-the serosal compartment ( J ms ) and in the opposite direction ( J sm ) were examined in Ussing chambers with 14 C-PhIP as radiotracer and in the absence of electrochemical gradients. Under these experimental conditions, significant negative net flux rates ( J net  =  J ms  −  J sm ) can only be explained by an active secretion of PhIP into the luminal compartment, and such an effect was observed in the rat distal colon, but not in the proximal jejunum. Moreover, the data obtained suggest that the breast cancer resistance protein, the multidrug resistance protein 4 and P-glycoprotein are not involved in the active secretion of PhIP in the rat distal colon. The potential role of PhIP transport in colon carcinogenesis is discussed.