Lack of large intestinal carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine at low doses in rats initiated with azoxymethane.
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.
Doi
Kenichiro
K
Department of Pathology, Osaka City University Medical School, Osaka, Japan.
Wanibuchi
Hideki
H
Salim
Elsayed I
EI
Morimura
Keiichirou
K
Kinoshita
Anna
A
Kudoh
Shinzoh
S
Hirata
Kazuto
K
Yoshikawa
Junichi
J
Fukushima
Shoji
S
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
D001391:Azo Compounds; D002273:Carcinogens; D007093:Imidazoles; C001825:azomethane; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine