Itoh T, Suzuki T, Nishikawa A, Furukawa F, Takahashi M, Xue W, Sofuni T, Hayashi M
Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan.
Mutat Res. 2000 Jun 22;468(1):19-25. doi: 10.1016/s1383-5718(00)00036-x.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a heterocyclic amine found in cooked meat, is a strong mutagen in the Salmonella/microsome assay and was proven to be a hepatocarcinogen in rodents. We used the lacI transgenic (Big Blue(R)) mouse to investigate MeIQx genotoxicity in vivo. lacI mutant frequencies were examined in liver and colon after single intragastric administration of MeIQx (males) or 12 weeks of feeding in the diet (males and females). Micronucleus induction was monitored in the peripheral blood and cell proliferating activity was monitored by proliferating cell nuclear antigen (PCNA) immunostaining, but only after the intragastric administration. Intragastric treatment with MeIQx (100 mg/kg) did not increase mutant frequency (MF) in liver or colon but it did induce a slight but statistically significant increase in the incidence of micronucleated reticulocytes 48 h after the treatment. No apparent increase in PCNA-positive foci was observed in any of tissues analyzed 14 days after the treatment. Administration of MeIQx (300 ppm) in diet for 12 weeks, however, caused MF increases in liver and colon in male and female mice, with greater increases in the females. An increase was also obvious after 4 weeks, but only in females. The sex difference in MF is consistent with the fact that female mice are more susceptible to MeIQx carcinogenesis. These results demonstrated that in the transgenic mouse mutation assay, long-term feeding of MeIQx was more effective than single gastric exposures in revealing the compound's mutagenicity in the target organs of carcinogenicity and that sex differences in susceptibility can also be observed.
2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）是一种在熟肉中发现的杂环胺，在沙门氏菌/微粒体试验中是一种强诱变剂，并且已被证明是啮齿动物的肝致癌物。我们使用lacI转基因（大蓝（R））小鼠来研究MeIQx在体内的遗传毒性。在单次胃内给予MeIQx（雄性）或在饮食中喂养12周（雄性和雌性）后，检测肝脏和结肠中的lacI突变频率。在给予胃内给药后，监测外周血中的微核诱导情况，并通过增殖细胞核抗原（PCNA）免疫染色监测细胞增殖活性。胃内给予MeIQx（100mg/kg）并未增加肝脏或结肠中的突变频率（MF），但在处理后48小时确实诱导了微核网织红细胞发生率的轻微但具有统计学意义的增加。在处理后14天，在所分析的任何组织中均未观察到PCNA阳性灶有明显增加。然而，在饮食中给予MeIQx（300ppm）12周，导致雄性和雌性小鼠肝脏和结肠中的MF增加，雌性增加更为明显。4周后也有明显增加，但仅在雌性中。MF的性别差异与雌性小鼠对MeIQx致癌作用更敏感这一事实一致。这些结果表明，在转基因小鼠突变试验中，长期喂养MeIQx比单次胃内暴露在揭示该化合物在致癌靶器官中的诱变性方面更有效，并且也可以观察到易感性的性别差异。
