title: Intestinal absorption and cell transforming potential of PhIP-M1, a bacterial metabolite of the heterocyclic aromatic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).
abstract: Previous studies have shown that in the rat, the colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is only absorbed to a limited extent in the small intestines and that a major fraction of unmetabolised PhIP reaches the colon. Moreover, PhIP is extensively metabolised when incubated with human stool samples to a major derivative, 7-hydroxy-5-methyl-3-phenyl-6,7,8,9-tetrahydropyrido [3',2':4,5]imidazo[1,2-a]pyrimidin-5-ium chloride (PhIP-M1). In the present study, the uptake and transport of PhIP-M1 in Ussing chamber experiments, its cytotoxicity in the different segments of the Fischer 344 rat gut and its transforming potential in the BALB/c 3T3 cell transformation assay were analysed. At the most, 10-20% of the PhIP-M1 amount added to the mucosal compartment of the Ussing chambers per segment were absorbed within 90min. Therefore, the amount of PhIP-M1 detected in the tissues as well as in the serosal compartment of the Ussing chambers was extremely low. Moreover, human-relevant concentrations of PhIP-M1 were not cytotoxic and did not induce the malignant transformation of BALB/c 3T3 cells. In conclusion, even if one would assume that 100% of the daily amount of PhIP ingested by a human being is converted into PhIP-M1 in the colon, this concentration most probably would not lead to cytotoxicity and/or carcinogenicity in the colorectal mucosa.
authors.affiliation: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Nicken
authors.affiliation: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Willenberg
authors.affiliation: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Anne von
authors.initials: Av
authors.lastname: Keutz
authors.affiliation: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Leonie von
authors.initials: Lv
authors.lastname: Elsner
authors.affiliation: Institute of Food Chemistry and Food Biotechnology, Justus-Liebig-University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hamscher
authors.affiliation: Laboratory of Chemical Analysis, Department of Veterinary Public Health and Food Safety, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Lynn
authors.initials: L
authors.lastname: Vanhaecke
authors.affiliation: Department of Physiology, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
authors.affiliation: Department of Physiology, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Breves
authors.affiliation: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Nils Helge
authors.initials: NH
authors.lastname: Schebb
authors.affiliation: Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany. Electronic address: pablo.steinberg@tiho-hannover.de.
authors.forename: Pablo
authors.initials: P
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000378:metabolism* / Q000633:toxicity*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000378:metabolism* / Q000633:toxicity*; D011916:Rats, Inbred F344; D018570:Risk Assessment
chemical_list: C530128:7-hydroxy-5-methyl-3-phenyl-6,7,8,9-tetrahydropyrido(3',2'-4,5)imidazo(1,2-a)pyrimidin-5-ium; D007093:Imidazoles; D011743:Pyrimidines
keywords: Colon cancer; Cytotoxicity; Malignant cell transformation; PhIP-M1 transport; Ussing chamber