title: DNA adduct formation of 14 heterocyclic aromatic amines in mouse tissue after oral administration and characterization of the DNA adduct formed by 2-amino-9H-pyrido[2,3-b]indole (AalphaC), analysed by 32P_HPLC.
abstract: Heterocyclic aromatic amines (HAAs) are produced during cooking of proteinaceous food such as meat and fish. Humans eating a normal diet are regularly exposed to these food-borne substances. HAAs have proved to be carcinogenic in animals and to induce early lesions in the development of cancer. DNA adduct levels in mouse liver have been measured by 32P-HPLC after oral administration each of 14 different HAAs. The highest DNA adduct levels were detected for 3-amino-1-methyl-5H-pyrido[4,3-b]-indole (Trp-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-9H-pyrido[2,3-b]indole (AalphaC), respectively. To assess a relative risk in a human population, a relative risk index was calculated by combining the DNA adduct levels in mouse liver with human daily intake of heterocyclic amines in a US and in a Swedish population. Such calculations suggest that AalphaC presents the highest risk for humans, e.g. nine-fold higher compared with the most abundant amines in food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP). Therefore, the distribution of DNA adducts in different tissues of mouse was investigated after oral administration of AalphaC. The highest AalphaC-DNA adduct levels were found in liver (137 adducts/10(8) normal nucleotides) followed by heart, kidney, lung, large intestine, small intestine, stomach and spleen, in descending order. To characterize the chemical structure of the major DNA adduct, chemical synthesis was performed. The major DNA adduct from the in vivo experiments was characterized by five different methods. On the basis of these results, the adduct was characterized as N2-(deoxyguanin-8-yl)-2-amino-9H-pyrido [2,3-b]indole. Considering the abundance of AalphaC not only in grilled meat, but also in other products like grilled chicken, vegetables and cigarette smoke and in light of the results of the present study, it is suggested that the human cancer risk for AalphaC might be underestimated.
authors.affiliation: Department of Biosciences, Laboratory for Analytical Toxicology and Karolinska Institutet, Novum, SE-141 57 Huddinge, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Baranczewski
authors.forename: J A
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: L
authors.initials: L
authors.lastname: Moller
mesh_terms: D000284:Administration, Oral; D000588:Amines; D000818:Animals; D014408:Biomarkers, Tumor; D002243:Carbolines; D002273:Carcinogens; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002855:Chromatography, Thin Layer; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles; D008297:Male; D008460:Meat; D051379:Mice; D009153:Mutagens; D009369:Neoplasms / Q000139:chemically induced*; D012306:Risk; D013053:Spectrophotometry; D013997:Time Factors; D014018:Tissue Distribution; D014466:Ultraviolet Rays
chemical_list: D000588:Amines; D014408:Biomarkers, Tumor; D002243:Carbolines; D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D009153:Mutagens; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole