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

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.
Carcinogenesis (Impact Factor: 5.33). 11/2010; 32(2):233-9. DOI: 10.1093/carcin/bgq235
Source: PubMed


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 N2-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.

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    • "2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic aromatic amines (HAAs) formed during thermal processing of proteinaceous foods, such as cooked beef, pork, chicken, and fish (Skog, Johansson, & Jägerstad, 1998). This HAA produces colon, prostate, and mammary gland tumors in rodents (Alaejos, Pino, & Afonso, 2008; Cheung, Loy, Li, Liu, & Yang, 2011; Choudhary, Sood, Donnell, & Wang, 2012), and the International Agency for Research on Cancer (IARC) has concluded that there is sufficient evidence in experimental animals for PhIP carcinogenicity (IARC, 1993). In addition, this compound is also considered as possibly carcinogenic to humans (IARC, 1993). "
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