Nine 3-allyl-5-substituted 2-thiohydantoins (ATH-amino acids) which were prepared from allyl isothiocyanate (AITC) and amino acids were studied for their antimutagenic activities against 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and 4-nitroquinoline 1-oxide (4-NQO) using the Ames assay. The assay against IQ was performed on S. typhimurium TA98 in the presence of a metabolic activation system (S9 mix) and that against 4-NQO was carried out on S.typhimurium TA100 in the absence of S9 mix. When ATH-amino acids except for that prepared from AITC and aspartic acid were simultaneously treated with the bacterial strain and IQ, an inhibition of IQ mutagenicity was observed. Also, all ATH-amino acids showed a suppressive effect on 4-NQO mutagenicity when the bacterial strain was incubated in the presence of both 4-NQO and ATH-amino acids. In contrast, little antimutagenic effect was observed when ATH-amino acids were added to the bacterial strains which has been pretreated with a mixture of IQ and S9 mix or only 4-NQO. These results suggest that ATH-amino acids are capable of acting as inhibitors of the S9 mix-mediated activation of IQ and/or as modulators of the direct-acting mutagen, 4-NQO.

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Airborne particles (n=541) , river waters (n=541) and surface soils (n=544) were collected from five geographically different regions of Japan (Hokkaido, Kanto, Chubu, Kinki and Kyushu regions) between 1996 and 2003. Extracts from those samples were measured and compared by a pre-incubation method using Salmonella typhimurium strains and a standard reference. Airborne particles were collected by high volume air samplers. All organic extracts of airborne particles except for some of those from Kinki region were mutagenic toward both TA98 and TA100 strains with and without S9 mix. Higher mutagenicity of airborne particulate extracts was observed for the samples collected at sites in heavy traffic areas and nearby industrial steel works. Mutagenic activity of airborne particles showed a gradual decrease over the period of the 7 years. Most of the blue rayon-absorbed materials from river waters exerted strong mutagenicity toward YG1024 strain with S9 mix, and the potencies varied widely among sampling sites. Blue rayonabsorbed materials showed no strong mutagenicity in TA100 or YG1029 strains, with or without S9 mix. Non-agricultural surface soils were collected from roadsides, parks and other open areas from each region. All organic extracts of surface soils were mutagenic toward either TA98 or TA100 strains with or without S9 mix. Mutagenic activities of surface soil extracts showed a wide range, and the effect of additional S9 mix on the activities depended on samples.

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Organochemical studies on food-derived mutagenic/carcinogenic components were described. Regulation of formation of carcinogenic nitrosamines in the reaction of secondary amines with nitrite under acidic conditions by food factors was described: stimulation by ethanol and suppression by unsaturated fatty acids and protein digests. Unique mutagenic diazo compounds produced in the reaction of monophenolics with nitrite generated carbon-centered radicals that bound to the base moieties of DNA molecules and caused DNA single strand breaks. The nitrate content in Japanese vegetables was high enough to produce nitrosamines in stomach. Nitric oxide generated in the body may produce nitrosamines and reactive oxygen species under neutral conditions. Mutagenic/carcinogenic heterocyclic amines were found in processed foods, smoked-dried bonito meat, roasted coffee beans and charred egg. Loss of water increased the mutagenicity of heated meats. Reduction of heterocyclic amines in cooked hamburger was successful by suppressing intermediary pyrazine cation radical in two ways: addition of an appropriate amount of sugar or onion, and addition of ascorbate or erythorbate. Food reductones, hydroxyfuranones in soy sauce and Maillard reaction mixtures and hydroxyhydroquinone in coffee, generated reactive oxygen species in vitro to cause DNA single strand breaks. The reductones induced minor DNA damage in vivo, but caused increased type I and IV allergy responses.

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The mutagenicities of methyl, ethyl, isopropyl, and butyl methanesulfonates and the corresponding alkylderivatives of N-nitrosoureas were examined using E. coli Hs30R strain deficient in the excision repair system. Their mutagenic capacities were standardized by converting the experimentally obtained mutation frequencies into those per unit of the concentration-time integrated dose with various dimensions, μM×h, mM×h, and M×h. The mutation frequencies under various conceptual exposure conditions were computed by using those at unit integrated dose, on the assumption that the dose-response relation is linear on a log-log scale.
An attempt was made to establish a procedure for kinetic formulation of the mutagenic chemical modification of the mutational target(s). Using the proposed kinetic formulation, a quantitative analysis was made of the temperature dependence of mutation frequency in terms of the activation energies for mutagenic modification induced in the cell by mutagens. E. coli Hs30R strain was treated with alkyl methanesulfonates and N-alkyl-N-nitrosoureas at 37, 25, and 15°C for 1 hour and the induced mutation frequencies were normalized in terms of the concentration-time integrated dose. The plot of the normalized mutation frequency versus the reciprocal of the reaction temperature gave a straight line which corresponds to the Arrehnius plot, enabling us to estimate the apparent activation energy of the initial chemical event leading to mutation.
In order to study the mutagenic interaction between two chemicals, an analytical method for the classification of the mutagenic interactions as “equivalent” or “independent” is proposed. The mutation frequencies induced by simultaneous (combined) treatments of Salmonella typhimurium TA100 with two simple alkylating agents were compared with those induced by separate treatments with the two mutagens. Furthermore, the comparison was made of the frequencies of micronucleated reticulocytes (MNRETs) produced in ddY mice treated with model chemicals such as alkylating agents, spindle poisons, and an oxidizing agent. The results indicate that the analytical method proposed here is appropriate to evaluate the combined effects of chemicals both in bacterial mutagenesis and micronucleus induction.

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Norharman, widely distributed in our environment including cigarette smoke and cooked foods, is not mutagenic to Salmonella strains, but becomes mutagenic to S. typhimurium TA98 and YG1024 with S9 mix in the presence of aromatic amines, such as aniline and o-toluidine. Regarding mechanisms of the co-mutagenic action of norharman with aniline, a mutagenic compound, aminophenylnorharman (APNH) is produced by their interaction, and converted to the hydroxyamino derivative which eventually forms the DNA adduct, dG-C8-APNH, and this induces mutations. Other aminophenyl-β-carboline compounds, such as amino-3’-methylphenylnorharman (3’-AMPNH), amino-2’-methylphenylnorharman (2’-AMPNH), aminophenylharman (APH) and amino-3’-methylphenylharman (AMPH), have also been found on reaction of norharman or harman with aniline or toluidine isomers. These compounds showed mutagenic and clastogenic actions in bacterial and mammalian cells. Among them, APNH demonstrated the most potent activity, and it was most extensively studied. When APNH was fed at 10—50 ppm in the diet for 4 weeks to F344 rats, the numbers and areas of liver preneoplastic lesions, GST-P positive foci, were significant. This suggests that APNH would induce liver tumors in rats. Since, APNH was detected in 24 hr urine of rats simultaneously administered with norharman and aniline by gavage, it is likely also to be produced from norharman and aniline in the human body. Therefore, it is conceivable that APNH is a new type of endogenously formed mutagen/carcinogen, involved in human carcinogenesis.

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