Rapid induction of colon carcinogenesis in CYP1A-humanized mice by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate.

Abstract

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine produced during the cooking of meats and fish, is suspected to be a human carcinogen. Metabolic activation of PhIP is primarily mediated by the enzyme cytochrome P450 (CYP) 1A2. Metabolism of PhIP by CYP1A2 differs considerably between humans and rodents, with more N(2)-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans. Transgenic CYP1A-humanized mice (hCYP1A-mice), which have the human CYP1A1 and CYP1A2 genes but lack the murine orthologs Cyp1a1 and Cyp1a2, provide an excellent opportunity to develop a relevant model to study dietary-induced colon carcinogenesis. The treatment with 200 mg/kg PhIP by oral gavage, followed by 1.5% dextran sodium sulfate (DSS) in the drinking water for 7 days, was found to be an effective combination to induce colon carcinogenesis in hCYP1A-mice. Tumor multiplicity at week 6 was calculated to be 3.75 ± 0.70 and for week 10 was 3.90 ± 0.61 with 80-95% of the tumors being adenocarcinomas. No tumors were found in the similarly treated wild-type mice. Western blots revealed overexpression of β-catenin, c-Myc, cyclin D1, inducible nitric oxide synthase and cyclooxygenase-2 in colon tumor samples. Strong nuclear localization of β-catenin was observed in tumors. These results illustrate that PhIP and DSS combination produces rapid colon carcinogenesis in hCYP1A-mice and this is an effective model to mimic human colon carcinogenesis.

• Authors: Connie Cheung, Shea Loy, Guang Xun Li, Anna B Liu, Chung S Yang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 32 Issue 2 Pg. 233-9 (Feb 2011) ISSN: 1460-2180 [Electronic] England
• PMID: 21081470 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carcinogens
• Imidazoles
• beta Catenin
• Dextran Sulfate
• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2

Topics

• Animals
• Biotransformation
• Carcinogens (toxicity)
• Colonic Neoplasms (chemically induced, mortality)
• Cytochrome P-450 CYP1A1 (physiology)
• Cytochrome P-450 CYP1A2 (physiology)
• Dextran Sulfate (toxicity)
• Female
• Humans
• Imidazoles (pharmacokinetics, toxicity)
• Male
• Mice
• Mice, Inbred C57BL
• Survival Rate
• beta Catenin (genetics)