TY - JOUR TI - The development of a model of PhIP-induced colon carcinogenesis in CYP1A2-humanized mice DO - https://doi.org/doi:10.7282/T37W6C8N PY - 2010 AB - The dietary carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) is considered one of the most abundant heterocyclic amines formed during the cooking of meats and fish. PhIP is metabolically activated to its carcinogenic form primarily by the human Cytochrome P450 enzyme, CYP1A2; whereas in rodents, PhIP is detoxified by the Cyp1a2 mouse ortholog. This metabolic activation is followed by esterification to produce activated esters that can bind to DNA to form adducts. PhIP-DNA adducts have been identified in various tissues of mice and in the colon of humans. PhIP has also demonstrated carcinogenicity in rodents, preferentially in the colons of rats and lymphatic system of mice. Through the use of a recently generated transgenic mouse model consisting of a human CYP1A1/1A2 gene insert on a mouse Cyp1a1/1a2 knockout background, we have developed a PhIP-induced humanized model of colon carcinogenesis. Male and female hCYP1A2 mice were given various combinations of PhIP (100mg/kg or 200mg/kg) by oral gavage without or with DSS (1% or 1.5%) in the drinking water for one week. We observed a single dose of PhIP (200mg/kg) followed by one week administration of dextran sodium sulfate (1.5%) in the drinking water of the hCYP1A2 mice to be the most effective treatment combination to induce colonic adenocarcinomas, with cancer formation in 6 weeks. In other treatment groups, ACF's were found to be present in the colons of mice treated with 100mg/kg of PhIP + 1% DSS as early as 6 weeks and in mice treated with 200mg/kg of PhIP without DSS as early as 12 weeks. In contrast, colonic neoplasms were not observed in C57BL/6J wild-type mice in any of the treatment groups. Pathological analysis of colonic tissue from hCYP1A2 mice treated with 200mg/kg of PhIP + 1.5% DSS revealed severe inflammation, a hyperplastic epithelial lining and an infiltration of leukocytes in the submucosal layer of the colon. Immunohistochemical analysis indicated that colonic neoplasms were associated with nuclear accumulation of β-catenin resembling mutations commonly found in human colon neoplasms. These results suggest that PhIP in combination with DSS in the hCYP1A2 mice is a good short-term animal model to study colon carcinogenesis. KW - Cell and Developmental Biology KW - Transgenic mice--Diseases KW - Colon (Anatomy)--Cancer--Pathophysiology KW - Colon (Anatomy)--Cancer--Prevention KW - Heterocyclic chemistry KW - Cytochrome P-450--Physiological effect LA - English ER -