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

Cancer Lett. 1998 Jan 30;123(2):167-72. doi: 10.1016/s0304-3835(97)00413-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Carcinogens / pharmacology
  • Colon / drug effects
  • Colon / pathology*
  • Enzyme Inhibitors / pharmacology
  • Imidazoles / pharmacology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology*
  • Male
  • Rats
  • Rats, Inbred F344
  • beta-Naphthoflavone / pharmacology*


  • Carcinogens
  • Enzyme Inhibitors
  • Imidazoles
  • beta-Naphthoflavone
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine