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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    ABSTRACT: In an attempt to understand the structural characteristics of phenolic compounds that favour the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation, this study analyzes the role of twenty-five phenolic compounds on the PhIP produced in phenylalanine/creatinine/oxidised lipid reaction mixtures. The results showed that phenols having two hydroxy groups at meta positions of the aromatic ring were the most efficient inhibitors. The presence of alkyl or carboxylic groups as additional substituents in the aromatic ring slightly reduced the inhibitory effect. On the other hand, the introduction of additional hydroxy and amino groups mostly cancelled the inhibitory effect, which was also mostly absent in ortho and para dihydroxy derivatives. In complex phenols, the presence of several rings with opposite effects produced a reduced inhibitory effect. All these results suggest that it is possible to predict if a phenolic derivative will inhibit the formation of PhIP, or not, based on its structure.
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    ABSTRACT: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e., N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts/10(8) deoxynucleosides), whereas adduct levels in liver were ∼3.5-fold lower. Whereas no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average ∼2-fold lower in extrahepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was ∼8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver.
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