The hepatocarcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a carcinogen contained in fried meat and fish, was examined in the medium-term rat liver carcinogenicity bioassay. Induction of DNA-MeIQx adducts occurred with low doses of the chemical, followed by increasing doses by elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in DNA and lacI gene mutations, which might have been related to the initiation of carcinogenesis by MeIQx. Further elevation of the MeIQx dose was shown to cause the formation of glutathione S-transferase placental form (GST-P) positive foci in the liver, a well-known preneoplastic marker in rat hepatocarcinogenesis. In studies with N-nitrosocompounds such as N-nitrosodiethylamine and N-nitrosodimethylamine, no induction of GST-P positive foci was observed after their administration at low doses. When the carcinogenicity of a well-known colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was examined, PhIP-DNA adduct formation was observed after treatment with low doses, while only high doses of the chemical were found to induce aberrant crypt foci (ACF), which are a surrogate marker of preneoplastic lesions in the colon. In experiments with potassium bromate, carcinogenicity, mutagenicity, and 8-OHdG formation in the rat kidney were observed only after administration at high dose. From these results, the genotoxic carcinogens were concluded to have a threshold, at least practical, with respect to their carcinogenicity.
Animal studies have revealed that tea flavonoids, known as catechins, have the potential to prevent cancer. We investigated the genotoxicity of the 4 main green tea catechins, namely, (−)-epigallocatechin gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-epicatechin (EC), using the comet assay in Chinese hamster CHL/IU cells. By measuring the percent of DNA in the comet tail, we concluded that EC, ECG, and EGCG did not induce biologically significant DNA damage. In contrast, EGC induced strong DNA damage at concentrations of 100 μM or higher. We further examined the genotoxic ability of EGC by the reverse mutation assay and the in vitro chromosome aberration test. The reverse mutation assay, revealed a maximum of 1.8-fold increase in the mean number of revertant colonies at 5000 μg/plate of EGC as compared to the number of colonies in the solvent control in Escherichia coli WP2uvrA/pKM101. EGC caused chromosome aberrations at low frequency in CHL/IU cells at a concentration of 200 μM. We concluded that EGC was weakly mutagenic in bacterial and mammalian cells.
Epidemiological evidence indicates that cigarette smoke is harmful to human health. Mainstream cigarette smoke has already been demonstrated to induce tissue and cellular damage in animal models. In the present study, we examined the toxicity of environmental cigarette smoke (ECS) by exposing Drosophila melanogaster larvae from urate-null and wild-type strains to ECS for 3 or 6 h at the third instar stage. We then determined survival to adulthood and the fecundity of adult females that survived larval ECS exposure. The survival of the urate-null strain, but not the wild-type strain, decreased significantly in an exposure-dependent manner. Moreover, the fecundity of treated urate-null, but not wild-type, females decreased significantly relative to the control level, irrespective of mating partner exposure to ECS at the larvae stage. These results demonstrate the killing effect and reproductive toxicity of ECS on urate-null larvae of Drosophila. Since the urate-null strain is known to be sensitive to oxidative agents, we propose that the main cause of the observed toxic effects of ECS is oxidative stress.
Recently, it has become necessary to increase the progress of research studies into drug discovery because of the introduction of combinatorial chemistry and robotics. Therefore, genotoxicity screening assays which can be conducted with a small amount of compound, in a short time, and which can predict the results of regulatory genotoxicity tests for pharmaceuticals are required in the early stage of research. The bacterial reverse mutation test (Ames test) is a regulatory genotoxicity test and is conducted in the early stage of non-clinical safety studies. Morita established a high throughput fluctuation Ames test using 384-well plates with Salmonella typhimurium TA100 and TA98 (Environ. Mutagen Res. 2003, 25: 23-31), which is referred to as original FAT in the present study. Here, we report an improved high throughput fluctuation Ames test (improved FAT). The improved FAT indicated a higher positive response than the original FAT in several mutagens. Furthermore, we evaluated the improved FAT with TA100 and TA98 using 40 National Toxicology Program (NTP) chemicals. As a result, there was 80.0% (32/40) concordance between the Ames test and the improved FAT. In conclusion, the improved FAT can predict the results of the Ames test with high concordance (especially its negative specificity). The improved FAT requires a much smaller amount of test chemicals than the Ames test (i.e., 5 mg vs 100 mg when using two tester strains) and is able to be automated. Thus, the improved FAT is considered to be useful as a screening test in the early stage of drug discovery.
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