Human exposure to carcinogenic heterocyclic amines and their mutational fingerprints in experimental animals.
Heterocyclic amines (HCAs) are mutagens/carcinogens to which humans are exposed on almost a daily basis. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) is the most abundant of the various carcinogenic HCAs (present at a level of 0.56 to 69.2 ng/g of cooked meat or fish), with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) following it at 0.64 to 6.44 ng/g. HCAs have been found in the urine of healthy people who consume ordinary diets, while patients receiving parenteral alimentation lack, for example, PhlP and MelQx in their urine. Based on the concentrations of PhlP and MelQx in urine samples from 10 healthy volunteers, daily intake of MelQx in Japanese was calculated to be 0.3 to 3.9 micrograms/person, while that of PhlP was 0.005 to 0 micrograms. The Japanese consume more MelQx than Americans, whereas Japanese intake of PhlP was about one-third that of Americans. MelQx-DNA adducts have also detected in Japanese Kidney, colon, and rectum samples using the 32P-postlabeling method followed by identification using high-performance liquid chromatography (HPLC) analysis; the levels were 0.18, 1.8, and 1.4 per 10(9) nucleotides, respectively. In addition, we elucidated the mutational fingerprints of Phlp by analyzing Apc mutations in rat colon cancers induced by this carcinogen. Four of eight tumors had a total of five mutations in the Apc gene, four of which featured a guanine deletion from 5'-GTGGGAT-3' sequences. This specific mutation spectrum may be used as a fingerprint of PhlP in evaluating its risk potential for human colon carcinogenesis. Mutations were not found in similar 2-amino-3-methylimidazo[4,5-f]quinoline-induced colon lesions. Microsatellite instability was detected in both colon and mammary tumors induced by PhlP. The mechanisms involved in this development of microsatellite instability in PhlP. The mechanisms involved in this development of microsatellite instability in PhlP-induced cancers remain to be elucidated.
Nagao
M
M
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan. mnagao@gan.ncc.go.jp
Wakabayashi
K
K
Ushijima
T
T
Toyota
M
M
Totsuka
Y
Y
Sugimura
T
T
D000588:Amines / Q000633:toxicity* / Q000652:urine; D000818:Animals; D002274:Carcinogens, Environmental / Q000032:analysis / Q000633:toxicity*; D018736:DNA Adducts; D004781:Environmental Exposure; D005506:Food Contamination; D006571:Heterocyclic Compounds / Q000633:toxicity* / Q000652:urine; D006801:Humans; D007093:Imidazoles / Q000633:toxicity / Q000652:urine; D009153:Mutagens / Q000032:analysis / Q000633:toxicity*; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics; D011810:Quinoxalines / Q000633:toxicity / Q000652:urine
D000588:Amines; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D006571:Heterocyclic Compounds; D007093:Imidazoles; D009153:Mutagens; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine