Environmental factors exert important influences on cancer development in humans. Cancer is now one of the major causes of death in our country, and it is necessary to search for mutagens and carcinogens in our environment to obtain information for evaluation of relationships with cancer patterns. My group has been involved in the identification of novel types of environmental mutagens and carcinogens and also in the study of mechanisms underlying colon carcinogenesis in rodents. The following results were obtained: 1) various kinds of mutagenic and carcinogenic heterocyclic amines were identified in cooked foods; 2) aminophenylnorharman was identified as a mutagenic compound formed from norharman and aniline in the presence of S9 mix; 3) mutagens and carcinogens were shown to be produced by the reaction of environmental aromatic compounds with nitrite; 4) eight kinds of phenylbenzotriazole compounds were isolated and identified as mutagens from river water in Japan; 5) enhancing effects of hyperlipidemia were demonstrated in intestinal carcinogenesis. In this review, roles of environmental factors in cancer development and related approaches to possible cancer prevention in humans are discussed.
Carcinogenic and mutagenic N-nitrosodialkylamines exist in our environment. In order to study the biological and chemical properties of the activated form of carcinogenic N-nitrosodialkylamines, highly unstable α-hydroxy nitrosamines were synthesized through deoxygenation of the corresponding α-hydroperoxy nitrosamines. Furthermore, active nitrosamines such as α-hydroperoxy, α-phosphonooxy, and α-acetoxy nitrosamines were also synthesized along with alkanediazohydroxides, which are activated products of α-hydroxy nitrosamines. The activity of all these active nitrosamines is highly dependent upon the alkyl groups in the N-nitrosodialkylamines. We demonstrate that α-hydroxylation is the key step in the metabolic activation of N-nitrosodialkylamines. Using chemical models for cytochrome P450, we isolated a mutagenic agent capable of alkylating DNA. Based on the chemistry of N-nitrosamines, we found some new possible anticancer lead compounds that have an N-nitroso group as an alkylating moiety and tricyclic aromatic rings as a DNA intercalating moiety.
Transgenic rodent mutation assays are useful models for investigating the genotoxicity of chemicals in vivo. Transgenic gpt delta mice contain multiple copies of chromosomally integrated lambda EG10 phage shuttle vector, which contains reporter genes that allow detection of mutations. This system can identify both point mutations by the gpt assay (6-thioguanine selection) and certain types of deletions using the Spi− assay. Transgenic gpt delta rats, which have the same lambda EG10 DNA copies as gpt delta mice, have also been developed. The average spontaneous gpt mutant frequency (MF) in both gpt delta mice and rats is approximately 4.5×10-6. In the Spi− assay, the average spontaneous Spi− MF is approximately 2.7×10-6 in gpt delta mice, similar to that of gpt delta rats. More than 20 chemicals and irradiations have been analyzed with these systems, and this review summarizes the MFs and treatment conditions. The data demonstrate that these transgenic rodent models are useful for detection and analysis of point mutations and deletions in vivo.
Variants of the error-prone gene, mucAB, were found in Escherichia coli plasmids from 3 out of 63 healthy Japanese donors. As compared with mucAB of pKM101, one contained unaltered mucA only, while two others contained full-sized, mutated mucAB with mutation-enhancing activity in E. coli. Possible interaction between bacterial plasmid genes and host humans was discussed.
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