Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Accelerated PublicationA new approach to risk estimation of food-borne carcinogens — heterocyclic amines — based on molecular information
Introduction
The clarification of what agents cause human cancers has and continues to be the goal of our studies. I, in collaboration with many scientists, have been working for more than 20 years on food mutagens, focusing especially on heterocyclic amines (HCAs) that are produced by cooking meat and fish. Here, I describe a brief overview of the data on mutagenic/carcinogenic HCAs to which humans are exposed on a daily basis.
In 1966, we established the carcinogenicity of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) [1], which had been recognized to be a strong mutagen. At that time, the link between carcinogenicity and mutagenicity was not well-appreciated and only a limited number of compounds had been recognized to be mutagenic carcinogens [2]. With our results for MNNG, we were able to add one compound to the list. Dr. Ames made an important contribution to this area by developing the Salmonella assay [3], and using this method to examine more than 200 chemicals, we rapidly found that a very good overlap exists between mutagen and carcinogen groups [4], [5]. This provided support for the Salmonella test as an appropriate method to identify causative agents for human cancers.
Section snippets
Mutagens in foods
One third of people in developed countries die of cancers and there is abundant evidence that environmental factors are causative agents. On average, humans eat 15 tons dry weight of food in a lifetime and it is very plausible that food stuffs should contain carcinogens. Grilled, sun-dried fish is a typical Japanese dish and beefsteak is a typical Western one. Methanol extracts of the charred parts of fish and meat, and of the smoke condensates produced while cooking these foods and trapped on
DNA adducts, mutations and carcinogenicity
For genotoxic carcinogens, the formation of DNA adducts is crucially important and without DNA adduct formation, genotoxic carcinogens usually do not induce cancers [37], [38]. To detect DNA adducts, the 32P-postlabeling method developed by Randerath et al. [39] is very suitable. We further improved this method to obtain a single form of DNA adduct as a single spot using thin layer chromatography (TLC), the original method yielding multiple spots from a single adduct form due to incomplete
Genetic factors involved in cancer susceptibility
Perusal of “Cancer Incidence in the Five Continents”, published by IARC [54], suggests that the Japanese are genetically susceptible to colon carcinogenesis. Although the incidence of colon cancer in Japanese in Japan is lower than that of Caucasians in the US, the value for Japanese in Hawaii is higher than that of Caucasians in the same country. The data indicate that the eating habits of the Japanese in Hawaii are well-Westernized, and that they are more susceptible to both stomach and colon
Signature mutations and their application for evaluation of HCA risk to human
The colon tumors induced by PhIP or IQ, another HCA, do not appear to have mutations in the ras or p53 genes [56]. However, 50% of these induced by PhIP was found to have Apc gene mutations, along with 17% of IQ-induced tumors [57]. The remaining tumors had mutations in the β-catenin gene [58]. Therefore, the major signaling pathway altered in tumors induced by HCAs is the same as that involved in human colon cancers where Wnt signaling plays a major role. Further, interestingly, all five
Acknowledgements
Most of studies described above were performed in the National Cancer Center Research Institute, in collaboration with Japanese colleagues, especially Dr. Sugimura as my supervisor and other leading scientists including Drs. Ito, Takayama, Kosuge, Shudou, Wakabayashi, Ushijima, Nakagama from Japan and Drs. Weisburger, Adamson and Snyderwine from the US. I express my gratitude to these collaborators and other individuals throughout the world for their help. I am also grateful for encouragement
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