College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki, Japan.
Mutat Res. 2020 May-Dec;821:111709. doi: 10.1016/j.mrfmmm.2020.111709. Epub 2020 May 23.
We have previously reported that quinoline increased the mutation frequency of the cII gene in the liver of lambda/lacZ transgenic mice (Muta™Mouse), and G:C to C:G transversions were the molecular signature of quinoline-induced mutations. 4-Methylquinoline (4-MeQ) has the highest mutagenicity among quinoline and isomeric methylquinolines according to the Ames test using Salmonella typhimurium TA 100, in the presence of rat liver microsomal enzymes. In this report, we examined the effect of 4-MeQ on mutagenesis in the lambda cII gene in the liver of the Muta™Mouse, and we analyzed the sequences of the mutated genes. The mutation frequency of the liver cII gene was seven times higher in 4-MeQ-treated mice than in control mice. Sequence analysis revealed that 4-MeQ primarily induced G:C to C:G transversions (37 of 45). The specificities of 4-MeQ for target organ and mutation pattern were very consistent with those of quinoline. Thus, we showed that 4-MeQ was also genotoxic in the liver of the Muta™Mouse, and as with quinoline, the G:C to C:G transversion was the molecular signature of the 4-MeQ-induced mutations.
我们之前曾报道，喹啉可增加 lambda/lacZ 转基因小鼠（Muta™Mouse）肝脏中 cII 基因的突变频率，G:C 到 C:G 的颠换是喹啉诱导突变的分子特征。根据含有大鼠肝微粒体酶的鼠伤寒沙门氏菌 TA100 的 Ames 试验，在喹啉及其同系物甲基喹啉中，4-甲基喹啉（4-MeQ）的致突变性最高。在本报告中，我们研究了 4-MeQ 对 Muta™Mouse 肝脏中 lambda cII 基因致突变性的影响，并分析了突变基因的序列。与对照组相比，4-MeQ 处理组小鼠肝脏 cII 基因的突变频率高 7 倍。序列分析显示，4-MeQ 主要诱导 G:C 到 C:G 的颠换（45 个突变中有 37 个）。4-MeQ 对靶器官和突变模式的特异性与喹啉非常一致。因此，我们表明 4-MeQ 也可引起 Muta™Mouse 肝脏的遗传毒性，与喹啉一样，G:C 到 C:G 的颠换是 4-MeQ 诱导突变的分子特征。
