Herzog C R, Schut H A, Maronpot R R, You M
Department of Pathology, Medical College of Ohio, Toledo 43699.
Mol Carcinog. 1993;8(3):202-7. doi: 10.1002/mc.2940080311.
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is a very potent mutagen that is carcinogenic in rodents and nonhuman primates. IQ-induced CDF1 mouse lung and liver tumors were examined for activated Ki-ras and Ha-ras genes, respectively. Polymerase chain reaction (PCR)-amplified target DNAs were analyzed for mutations of codons 12, 13, and 61 by single-strand conformation polymorphism (SSCP) and direct sequencing methods. All mutations were localized to codon 61 of the ras genes. Forty-nine of 54 lung tumors induced by IQ possessed activating Ki-ras mutations, as did 20 of 26 lung tumors from the vehicle-treated animals; 80% and 75% of these mutations, respectively, were A-->T transversions of the second nucleotide redundant. One lung adenoma from the IQ-treated group contained a tandem duplication of the sequence corresponding to codons 50-57 of the Ki-ras gene (unpublished observations). In addition, seven of 34 IQ-induced liver tumors harbored activating Ha-ras mutations: five were C-->A (G-->T) transversions at the first nucleotide, and two were A-->T transversions at the second nucleotide of codon 61. None of the 15 liver tumors collected from the vehicle-treated mice possessed Ha-ras mutations in codon 12, 13, or 61. These data indicate that IQ induces Ha-ras gene activation in CDF1 mouse liver tumors. The mechanisms of lung tumor induction by IQ, however, is obscured by the high frequency of Ki-ras A-->T mutations observed in both the IQ-induced and spontaneous lung tumors. The different ras mutational spectra in lung and liver tumors may suggest either that two different pathways of IQ metabolism exist in these organs or that IQ contributes to CDF1 lung tumorigenesis by a mechanism other than its direct interaction with the Ki-ras gene.
2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）是一种极具诱变作用的物质，对啮齿动物和非人类灵长类动物具有致癌性。分别检测了IQ诱导的CDF1小鼠肺肿瘤和肝肿瘤中激活的Ki-ras基因和Ha-ras基因。通过单链构象多态性（SSCP）和直接测序方法，对聚合酶链反应（PCR）扩增的靶DNA进行密码子12、13和61突变分析。所有突变均定位于ras基因的密码子61。IQ诱导的54个肺肿瘤中有49个具有激活的Ki-ras突变，载体处理动物的26个肺肿瘤中有20个也有该突变；这些突变中分别有80%和75%是第二个核苷酸冗余的A→T颠换。IQ处理组的一个肺腺瘤包含与Ki-ras基因密码子50-57相对应序列的串联重复（未发表的观察结果）。此外，34个IQ诱导的肝肿瘤中有7个含有激活的Ha-ras突变：5个是密码子61第一个核苷酸的C→A（G→T）颠换，2个是第二个核苷酸的A→T颠换。从载体处理小鼠收集的15个肝肿瘤中，没有一个在密码子12、13或61处有Ha-ras突变。这些数据表明IQ在CDF1小鼠肝肿瘤中诱导Ha-ras基因激活。然而，IQ诱导肺肿瘤的机制因在IQ诱导的和自发的肺肿瘤中均观察到高频的Ki-ras A→T突变而变得模糊不清。肺肿瘤和肝肿瘤中不同的ras突变谱可能表明在这些器官中存在两种不同的IQ代谢途径，或者IQ通过其与Ki-ras基因的直接相互作用以外的机制促进CDF1肺肿瘤发生。
