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

Arch Toxicol. 2013 May;87(5):895-904. doi: 10.1007/s00204-012-1006-0. Epub 2013 Jan 10.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Adenocarcinoma / chemically induced
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Animals
  • Biological Transport
  • Carcinogens / pharmacokinetics*
  • Carcinogens / toxicity
  • Colon / drug effects
  • Colon / metabolism*
  • Colon / pathology
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Enterocytes / drug effects
  • Enterocytes / metabolism*
  • Enterocytes / pathology
  • Imidazoles / pharmacokinetics*
  • Imidazoles / toxicity
  • Jejunum / drug effects
  • Jejunum / metabolism
  • Jejunum / pathology
  • Male
  • Multidrug Resistance-Associated Proteins / metabolism
  • Rats
  • Rats, Inbred F344

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcc4 protein, rat
  • Abcg2 protein, rat
  • Carcinogens
  • Imidazoles
  • Multidrug Resistance-Associated Proteins
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine