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A new approach to risk estimation of food-borne carcinogens — heterocyclic amines — based on molecular information

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Abstract

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 μg/day, predominantly to 2-amino-1-methyl-6-phenylimidazo[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.

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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