title: 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.affiliation: Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Cheung
authors.forename: Shea
authors.initials: S
authors.lastname: Loy
authors.forename: Guang Xun
authors.initials: GX
authors.lastname: Li
authors.forename: Anna B
authors.initials: AB
authors.lastname: Liu
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000401:mortality; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology*; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015996:Survival Rate; D051176:beta Catenin / Q000235:genetics
chemical_list: D002273:Carcinogens; D007093:Imidazoles; D051176:beta Catenin; D016264:Dextran Sulfate; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2