title: Lack of large intestinal carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine at low doses in rats initiated with azoxymethane.
abstract: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-week-old male F344 rats were subcutaneously injected twice with 15 mg/kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm(2) did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model.
authors.affiliation: Department of Pathology, Osaka City University Medical School, Osaka, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Doi
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
authors.forename: Elsayed I
authors.initials: EI
authors.lastname: Salim
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Anna
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Shinzoh
authors.initials: S
authors.lastname: Kudoh
authors.forename: Kazuto
authors.initials: K
authors.lastname: Hirata
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshikawa
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000633:toxicity*; D007414:Intestinal Neoplasms / Q000139:chemically induced; D007420:Intestine, Large / Q000187:drug effects*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D001391:Azo Compounds; D002273:Carcinogens; D007093:Imidazoles; C001825:azomethane; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine