Yamakage Kohji, Sui Hajime, Ohta Ryo, Toyoizumi Tomoyasu, Kawakami Kumiko, Matsumoto Hirotaka, Takahashi Toshitaka, Sasaki Kiyoshi, Ikezumi Mayu, Negishi Saki, Izumi Keisuke, Todoriki Setsuko, Takashi Kondo, Furuta Masakazu
Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
Mutat Res Genet Toxicol Environ Mutagen. 2014 Aug;770:95-104. doi: 10.1016/j.mrgentox.2014.04.021. Epub 2014 Jun 8.
The DNA-damaging and tumour-promoting effects of two 2-alkylcyclobutanones (2-ACBs), which are found in irradiated fat-containing foods, were investigated by use of the comet assay and in an azoxymethane (AOM)-induced colon-carcinogenesis study in rats, respectively. We conducted genotoxicity tests of 2-dodecylcyclobutanone (2-dDCB) and 2-tetradecylcyclobutanone (2-tDCB) according to the test guidelines for chemicals or drugs. In addition, a cell-transformation assay with Bhas 42 cells was performed to investigate their promoting potential in vitro. The Salmonella typhimurium mutagenicity assay (Ames test), conducted with five tester strains, revealed that neither 2-dDCB nor 2-tDCB possessed mutagenic activity. Moreover, both in the in vitro chromosomal aberration test on CHL/IU cells and the in vivo bone-marrow micronucleus test where mice were given 2-dDCB and 2-tDCB (orally, up to 2000 mg/kg bw/day), we did not detect any clastogenic effects. Furthermore, DNA strand-breaks were not detected in the in vitro comet assay with CHL/IU cells, and DNA adducts derived from 2-dDCB and 2-tDCB were not detected in the colon tissues of the mice used for the micronucleus tests, in rats from a repeated dose 90-day oral toxicity test (0.03% 2-tDCB in the diet), or in rats from the AOM-induced carcinogenesis study (0.025% 2-tDCB in the diet). An in vitro tumour-promotion assay with Bhas 42 cells revealed that the number of transformed foci increased significantly following treatment of cells in the stationary phase with 2-dDCB or 2-tDCB for 10 days. Our results indicate that neither 2-dDCB nor 2-tDCB were genotoxic chemicals. However, they exhibited promoting activity, at least in vitro, when Bhas 42 cells were continuously exposed to these chemicals at toxic doses.
通过彗星试验以及在大鼠的氧化偶氮甲烷（AOM）诱导的结肠癌发生研究中，分别对辐照含脂食品中发现的两种2-烷基环丁酮（2-ACB）的DNA损伤和促肿瘤作用进行了研究。我们根据化学品或药物的测试指南，对2-十二烷基环丁酮（2-dDCB）和2-十四烷基环丁酮（2-tDCB）进行了遗传毒性测试。此外，用Bhas 42细胞进行了细胞转化试验，以研究它们在体外的促癌潜力。用五种测试菌株进行的鼠伤寒沙门氏菌致突变性试验（Ames试验）表明，2-dDCB和2-tDCB均不具有诱变活性。此外，在对CHL/IU细胞进行的体外染色体畸变试验以及在给小鼠口服2-dDCB和2-tDCB（高达2000 mg/kg体重/天）的体内骨髓微核试验中，我们均未检测到任何致断裂效应。此外，在对CHL/IU细胞进行的体外彗星试验中未检测到DNA链断裂，在用于微核试验的小鼠结肠组织、重复剂量90天口服毒性试验（饲料中含0.03% 2-tDCB）大鼠的结肠组织或AOM诱导的致癌研究（饲料中含0.025% 2-tDCB）大鼠的结肠组织中，均未检测到源自2-dDCB和2-tDCB的DNA加合物。用Bhas 42细胞进行的体外肿瘤促进试验表明，用2-dDCB或2-tDCB处理静止期细胞10天后转化灶数量显著增加。我们的结果表明，2-dDCB和2-tDCB均不是遗传毒性化学品。然而，当Bhas 42细胞持续暴露于这些有毒剂量的化学品时，它们至少在体外表现出促癌活性。
