Hayashi S, Hong H H, Toyoda K, Ton T V, Devereux T R, Maronpot R R, Huff J, Sills R C
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Toxicol Pathol. 2001 Jul-Aug;29(4):422-9. doi: 10.1080/01926230152499908.
1-Amino-2,4-dibromoanthraquinone (ADBAQ) is an anthraquinone-derived vat dye, and a potent carcinogen in laboratory animals. In a 2-year study with dietary exposure to 10,000 or 20,000 ppm ADBAQ, increased incidence of forestomach and lung tumors were observed in B6C3F1 mice. The present study indentified genetic alterations in H-ras and K-ras proto-oncogenes in ADBAQ-induced tumors. Point mutations in ras proto-oncogenes were identified by restriction fragment length polymorphism, single-stranded conformational polymorphism analysis and cycle sequencing of polymerase chain reaction-amplified DNA isolated from paraffin-embedded squamous cell papillomas and carcinomas in the forestomach, and alveolar/bronchiolar adenomas and carcinomas in the lung. A higher frequency of ras mutations was identified in ADBAQ-induced forestomach (23/32, 72%) and lung tumors (16/23, 70%) than in spontaneous forestomach (4/11, 36%) and lung tumors (26/86, 30%). H-ras codon 61 CTA mutations were detected in (4/8, 50%) ADBAQ-induced forestomach squamous cell papillomas and (10/24, 42%) squamous cell carcinomas, but not in the spontaneous forestomach tumors examined. H-ras codon 61 CGA mutation (6/24, 25%) was also detected in ADBAQ-induced forestomach squamous cell carcinomas. K-ras codon 61 A to T transversions and A to G transitions were prominent in ADBAQ-induced lung alveolar/bronchiolar adenomas and alveolar/bronchiolar carcinomas. The major finding of A to T transversions or A to G transitions in forestomach and lung tumors suggests that ADBAQ or its metabolites target adenine bases in the ras proto-oncogenes and that these mutations play a dominant role in multi-organ
1-氨基-2,4-二溴蒽醌（ADBAQ）是一种蒽醌衍生的还原染料，在实验动物中是一种强效致癌物。在一项为期两年的饮食暴露于10000或20000 ppm ADBAQ的研究中，在B6C3F1小鼠中观察到前胃和肺部肿瘤的发生率增加。本研究确定了ADBAQ诱导的肿瘤中H-ras和K-ras原癌基因的遗传改变。通过限制性片段长度多态性、单链构象多态性分析以及对从石蜡包埋的前胃鳞状细胞乳头瘤和癌以及肺肺泡/细支气管腺瘤和癌中分离的聚合酶链反应扩增DNA进行循环测序，鉴定了ras原癌基因中的点突变。与自发的前胃肿瘤（4/11，36%）和肺部肿瘤（26/86，30%）相比，在ADBAQ诱导的前胃肿瘤（23/3,72%）和肺部肿瘤（16/23,70%）中鉴定出更高频率的ras突变。在ADBAQ诱导的前胃鳞状细胞乳头瘤（4/8，50%）和鳞状细胞癌（10/24，42%）中检测到H-ras密码子61 CTA突变，但在所检查的自发前胃肿瘤中未检测到。在ADBAQ诱导的前胃鳞状细胞癌中也检测到H-ras密码子61 CGA突变（6/24，25%）。K-ras密码子61从A到T的颠换和从A到G的转换在ADBAQ诱导的肺肺泡/细支气管腺瘤和肺泡/细支气管癌中很突出。在前胃和肺部肿瘤中A到T颠换或A到G转换的主要发现表明，ADBAQ或其代谢物靶向ras原癌基因中的腺嘌呤碱基，并且这些突变在多器官中起主导作用
