Modification of DNA is believed to be a key step in mutagenesis and carcinogenesis. Reactive oxygen species (ROS) generated by environmental factors can cause oxidative DNA damage. This review focused on the role of oxidative DNA damage in mutagenesis and carcinogenesis mediated by environmental factors. This research investigated the mechanism of DNA damage induced by environmental chemicals and dietary factors using 32P-labeled DNA fragments obtained from the c-Ha-RAS-1 protooncogene and the p16 and p53 tumor suppressor genes. In addition, the content of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) was measured by using a high performance liquid chromatograph equipped with an electrochemical detector. 8-oxodG is probably one of the most abundant DNA lesion formed during oxidative stress. Antioxidants are considered as the most promising chemopreventive agents against various human cancers. However, some antioxidants play paradoxical roles acting as “double-edged sword”. The present research also investigated the mechanism of DNA damage induced by antioxidants using human cultured cell lines and 32P-labeled DNA fragments. This review shows recent experimental results and discusses the mechanisms of oxidative DNA damage in relation to carcinogenesis.
Simultaneous administration of sodium nitrite (NaNO2) and ascorbic acid (AsA) induces weak oxidative DNA damage in forestomach epithelium and enhances forestomach carcinogenesis in F344 rats. To investigate the mutagenicity of the combination of NaNO2 and AsA, we conducted reverse mutation assays in E. coli WP2uvrA/pKM101 and cytogenetic assays in cultured Chinese hamster lung CHL/IU cells without a metabolic activation system. When WP2uvrA/pKM101 was preincubated with a combination of 78.1-5000 μg/plate NaNO2 and 5 mg/plate AsA in standard buffer (pH 7.4), the number of revertants slightly increased compared to treatment with NaNO2 alone. Performing the same experiment using pH 6.0 buffer, in which the buffer decreased to about pH 4.9 due to the acidity of AsA, demonstrated that the number of revertants markedly increased. Additional experiments showed that the mutagenicity of NaNO2 itself markedly increased at pH 5.0-5.5. These results suggest that the enhancement of the mutagenic activity of NaNO2 in pH 6.0 buffer is likely due to a pH-lowering effect of AsA. In the cytogenetic assays, no substantial increase in chromosomally aberrant cells was observed in cultures treated with NaNO2 or AsA alone for 3 h, but combined treatment with 5 mg/mL NaNO2 and 1.5-2.5 mg/mL AsA significantly increased chromosome aberrations. We concluded that simultaneous treatment with NaNO2 and AsA at high doses induced mutagenic or clastogenic damage to bacterial and mammalian cells and that such genotoxic damage probably contributed to forestomach carcinogenesis in rats treated with combined NaNO2 and AsA.
Precise evaluation of dose-response relationships at low doses is essential for proper risk assessment. It is commonly found that responses of more than background are not observed at very low doses, and the responses increase with dose increments to a maximum at high doses. Here, a variety of dose-response curves for a modified linear-no-threshold model were demonstrated with ordinary and logarithmic graphs. In general, the dose response was observed to be linear when repair or detoxification capacity was far smaller than the background response level, while “threshold-like” dose responses were observed when the capacity was large enough. However, linear increase in mutation frequency was still observed even below the “threshold-like” doses albeit a response per dose was very low. Mutagenicity data of N-methyl-N′-nitro-N-nitrosoguanidine and sodium azide to Salmonella typhimurium, reported by Sofuni et al. (Environ Mutagen Res. 2005; 27: 61), were applied to the model, as an example of estimation of various parameters and of evaluation of the mutation risk at low doses. Risk estimation from experimental data is discussed.
Kojic acid has been used for skin whitening as a cosmetic agent. Kojic acid is believed to be hepatocarcinogenic in mice. We conducted the comet assay in mouse and rat multiple organs to evaluate its in vivo genotoxic potential. Kojic acid induced dose-dependent DNA damage in ddY mouse stomach and liver and in Wistar rat stomach, liver, lung, and bone marrow after a single gavage administration at ≦1000 mg/kg. Its hepatic genotoxicity detected by the comet assay seems to contradict to absence of its hepatic tumor initiating activity revealed by the two-step carcinogenesis studies with mice and rats. However, considering the possibility that the sensitivity of the two-step carcinogenesis studies performed are not high enough to detect weak initiating activity of a chemical, it would be premature to conclude that its hepatic genotoxicity contradicts to the absence of initiating activity. In mice fed a diet containing 3% kojic acid for up to 10 days, DNA migration increased in the stomach after feeding for 2 days but it did not increased after feeding for 1 day and ≧4 days. In the colon, DNA migration after feeding of 3% kojic acid for 2 days was higher than the control values, but this increase was not statistically significant. In the stomach and colon, any statistically significant increases in DNA migration were not observed after feeding of 1.5% kojic acid. In the liver, DNA migration increased with feeding period and the increases after feeding of 3% and 1.5% kojic acid for ≧4 days and 6 days, respectively, were statistically significant. Our present results suggested good correlation between hepatocarcinogenicity of kojic acid and increasing tendency of its hepatic genotoxicity with dosing period when it is given to mice continuously in the diet.
April 03, 2017 There had been a system trouble from April 1, 2017, 13:24 to April 2, 2017, 16:07(JST) (April 1, 2017, 04:24 to April 2, 2017, 07:07(UTC)) .The service has been back to normal.We apologize for any inconvenience this may cause you.
May 18, 2016 We have released “J-STAGE BETA site”.
May 01, 2015 Please note the "spoofing mail" that pretends to be J-STAGE.