title: Comparative DNA adduct formation and induction of colonic aberrant crypt foci in mice exposed to 2-amino-9H-pyrido[2,3-b]indole, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and azoxymethane.
abstract: Considerable evidence suggests that environmental factors, including diet and cigarette smoke, are involved in the pathogenesis of colon cancer. Carcinogenic nitroso compounds (NOC), such as N-nitrosodimethylamine (NDMA), are present in tobacco and processed red meat, and NOC have been implicated in colon cancer. Azoxymethane (AOM), commonly used for experimental colon carcinogenesis, is an isomer of NDMA, and it produces the same DNA adducts as does NDMA. Heterocyclic aromatic amines (HAAs) formed during the combustion of tobacco and high-temperature cooking of meats are also associated with an elevated risk of colon cancer. The most abundant carcinogenic HAA formed in tobacco smoke is 2-amino-9H-pyrido[2,3-b]indole (AαC), whereas 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) is the most potent carcinogenic HAA formed during the cooking of meat and fish. However, the comparative tumor-initiating potential of AαC, MeIQ, and AOM is unknown. In this report, we evaluate the formation of DNA adducts as a measure of genotoxicity, and the induction of colonic aberrant crypt foci (ACF) and dysplastic ACF, as an early measure of carcinogenic potency of these compounds in the colon of male A/J mice. Both AαC and AOM induced a greater number of DNA adducts than MeIQ in the liver and colon. AOM induced a greater number of ACF and dysplastic ACF than either AαC or MeIQ. Conversely, based on adduct levels, MeIQ-DNA adducts were more potent than AαC- and AOM-DNA adducts at inducing ACF. Long-term feeding studies are required to relate levels of DNA adducts, induction of ACF, and colon cancer by these colon genotoxicants.
authors.affiliation: Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota.
authors.forename: Sangyub
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Guo
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Department of Veterinary Population Medicine, University of Minnesota, St. Paul, Minnesota.
authors.forename: M Gerald
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Gallaher
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008815:Mice, Inbred Strains; D009077:Mucins / Q000378:metabolism; D011804:Quinolines / Q000633:toxicity*; D059550:Toxicity Tests, Subchronic
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D009077:Mucins; D011804:Quinolines; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline; D001397:Azoxymethane
keywords: DNA adducts; aberrant crypt foci (ACF); azoxymethane; heterocyclic aromatic amines; mucin-depleted foci (MDF); sialomucin-expressing ACF; tobacco smoke