A new approach to risk estimation of food-borne carcinogens--heterocyclic amines--based on molecular information.
Identification of causative agents for human cancers is the goal of our studies. We analyzed ordinary foods for mutagenicity, using the well-established Salmonella test. Heating fish and meat yielded mutagens that require metabolic activation for exhibition of mutagenicity. Structural determination revealed these mutagens to be heterocyclic amines (HCAs), their precursors in some cases being creatin(in)e, sugars and amino acids. Ten HCAs so far examined have all proved carcinogenic in mice and rats, inducing cancers in various organs such as in the mammary glands, prostate, lung, colon, skin, bladder and liver. Human exposure to HCAs is 0.1-12 microg/day, predominantly to 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). For these types of genotoxic carcinogens, DNA-adduct formation is crucially important and PhIP-DNA adducts have been detected in human tissues. However, the amounts of individual HCAs ingested by humans may not be sufficient to induce cancers by themselves and many environmental factors have also been implicated in neoplasia in man, with other considerable inter-individual variation in susceptibility, e.g., to colon carcinogenesis. This is in line with results obtained by feeding different strains of rats with HCA. Studies using lacI transgenic mice and rats have revealed that DNA adducts do not directly correlate with mutant frequencies at the organ level, or cancer incidence. However, sequencing of the Apc gene of rat colon tumors induced by PhIP revealed that it induces a signature mutation of G deletion from the GGGA sequence. This type of mutation is found in the p53 gene of 0.3% human cancers having p53-somatic mutations, and it has been calculated that 3%-10% of the p53 mutations detected in human cancers could be ascribable to PhIP. Although there remains the possibility that other carcinogens involved in human carcinogenesis cause the same signature mutation, the available data point to an important role for PhIP.
Nagao
M
M
Tokyo University of Agriculture, Faculty of Applied Bioscience, Japan. mnagao@ncc.go.jp
D000588:Amines / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D020732:Cytogenetic Analysis; D018736:DNA Adducts; D005260:Female; D005502:Food; D020022:Genetic Predisposition to Disease; D006571:Heterocyclic Compounds / Q000633:toxicity*; D006801:Humans; D007093:Imidazoles / Q000633:toxicity; D008297:Male; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics*
D000588:Amines; D002273:Carcinogens; D018736:DNA Adducts; D006571:Heterocyclic Compounds; D007093:Imidazoles; D009153:Mutagens; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine