Induction of apoptosis in colonic epithelium treated with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and its modulation by a P4501A2 inducer, beta-naphthoflavone, in male F344 rats.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the mutagenic heterocyclic amines derived from cooked meat. In long-term experiments using rodents, carcinogenicity of PhIP in colon, mammary gland and prostate has been demonstrated. In this study, an experiment was designed to determine the apoptosis-inducing capacity of PhIP in colonic epithelium, a target organ for PhIP carcinogenicity, and possible modulating effects of beta-naphthoflavone (beta-NF), a P4501A2 inducer, on the apoptosis in rats. Out of eight groups of male F344 rats, four were given beta-NF in diet (1000 ppm) for a week beginning at 5 weeks of age. Four groups were given PhIP (100 mg/kg body weight) by gavage at 6 weeks of age. Twenty-four hours after the dosing of PhIP, cell death with typical morphology of apoptosis was apparent in the colon and the apoptotic index was significantly greater (P < 0.01) than of the control rats without exposure to PhIP. Prior administration of beta-NF caused significant acceleration of the induction of apoptosis by PhIP. Since PhIP requires metabolic activation by P4501A2 to exert genotoxic activities, the modulating effect of beta-NF on the PhIP-induced apoptosis will be through a P4501A2-dependent mechanism. Such assay of apoptotic indices in the colon may be useful not only for the evaluation of genotoxicity and/or the initiating capability of chemical agents with potentials for colorectal cancer, but also for the analysis of modifying agents on the carcinogenesis in the large bowel.
Hirose
Y
Y
First Department of Pathology, Gifu University School of Medicine, Japan.
Sugie
S
S
Yoshimi
N
N
Matsunaga
K
K
Hara
A
A
Mori
H
H
D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D019324:beta-Naphthoflavone / Q000494:pharmacology*
D002273:Carcinogens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019324:beta-Naphthoflavone; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine