Anna C H, Maronpot R R, Pereira M A, Foley J F, Malarkey D E, Anderson M W
Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Carcinogenesis. 1994 Oct;15(10):2255-61. doi: 10.1093/carcin/15.10.2255.
The frequency and mutation spectra of proto-oncogene activation in hepatocellular neoplasms induced by tetrachloroethylene, trichloroethylene and dichloroacetic acid were examined to help define the molecular basis for their carcinogenicity. H-ras codon 61 activation was not significantly different among dichloroacetic acid- and trichloroethylene-induced and combined historical and concurrent control hepatocellular tumors (62%, 51% and 69% respectively). The mutation spectra of H-ras codon 61 mutations showed a significant decrease in AAA and increase in CTA mutations for dichloroacetic acid- and trichloroethylene-induced tumors when compared to combined controls. The H-ras codon 61 mutation frequency for tetrachloroethylene-induced tumors was significantly lower (24%) than that of combined controls and also that of the two other chemicals. Mutations at codons 13 and 117 plus a second exon insert contributed 4% to the total H-ras frequencies for trichloroethylene and tetrachloroethylene. There was also a higher incidence of K-ras activation (13%) in tetrachloroethylene-induced tumors than in the other chemically induced or control tumors. Four liver tumors were found to contain insertions of additional bases within the second exon of K- or H-ras. These findings suggest that exposure to dichloroacetic acid, trichloroethylene and tetrachloroethylene provides a selective growth advantage to spontaneously occurring mutations in codon 61 of H-ras and, at the same time, is responsible for a small number of unique molecular lesions suggestive of either a random genotoxic mode of action or a non-specific result of secondary DNA damage. However, the absence of ras activation in many of the liver neoplasms suggests that alternative mechanisms are also important in B6C3F1 mouse hepatocarcinogenesis.
研究了四氯乙烯、三氯乙烯和二氯乙酸诱导的肝细胞肿瘤中原癌基因激活的频率和突变谱，以帮助确定它们致癌性的分子基础。在二氯乙酸和三氯乙烯诱导的以及合并的历史和同期对照肝细胞肿瘤中，H-ras密码子61激活情况无显著差异（分别为62%、51%和69%）。与合并对照相比，二氯乙酸和三氯乙烯诱导肿瘤的H-ras密码子61突变谱显示AAA突变显著减少，CTA突变增加。四氯乙烯诱导肿瘤的H-ras密码子61突变频率显著低于合并对照以及其他两种化学物质诱导的肿瘤（24%）。密码子13和117处的突变加上第二个外显子插入占三氯乙烯和四氯乙烯诱导肿瘤中H-ras总突变频率的4%。四氯乙烯诱导肿瘤中K-ras激活的发生率（13%）也高于其他化学物质诱导的或对照肿瘤。发现4个肝肿瘤在K-或H-ras的第二个外显子内有额外碱基插入。这些发现表明，接触二氯乙酸、三氯乙烯和四氯乙烯为H-ras密码子61的自发突变提供了选择性生长优势，同时导致了少数独特的分子损伤，提示可能存在随机的基因毒性作用模式或继发DNA损伤的非特异性结果。然而，许多肝肿瘤中不存在ras激活，这表明其他机制在B6C3F1小鼠肝癌发生中也很重要。
