Predominant K-ras codon 12 G --> A transition in chemically induced lung neoplasms in B6C3F1 mice.
Predominant K-ras codon 12 G --> A transition in chemically induced lung neoplasms in B6C3F1 mice.
复制标题
主要 K-ras 密码子 12 G --> B6C3F1 小鼠化学诱导肺肿瘤的转变。
DOI：
10.1080/01926230490260682
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发表时间：
2004
影响因子：
1.5
通讯作者：
Kim,Yongbaek
中科院分区：
文献类型：
--
作者：
Ton,Thai-VuT;Hong,Hue-HuaL;Anna,ColleenH;Dunnick,JuneK;Devereux,TheodoraR;Sills,RobertC;Kim,Yongbaek
根据国家毒理学计划在B6 C3 F1小鼠中进行的长期毒性和致癌性研究，2，2-双（溴甲基）-1，3-丙二醇（BMP）和四硝基甲烷（TNM）已被确定为致癌物。在暴露于312、625或1，250 ppm BMP饲料或通过吸入暴露于0.5或2 ppm TNM 2年后，与未暴露小鼠相比，在所有暴露浓度下观察到B6 C3 F1小鼠肺肿瘤发生率增加。本研究分别描述了BMP和TNM诱导的肺肿瘤中K-ras原癌基因的遗传改变，并将结果与相应对照小鼠的自发性肺肿瘤进行了比较。在BMP诱导的肺肿瘤中，K-ras突变的频率为57%（29/51），而在给药饲料对照小鼠的肺肿瘤中为15%（3/20），在TNM诱导的肺肿瘤中为54%（14/26），而在吸入对照小鼠的肺肿瘤中为60%（3/5）。K-ras密码子12第二个碱基的G → A转换（GGT → GAT）是BMP诱导的肺肿瘤（20/29）和TNM诱导的肺肿瘤（13/14）中最常见的K-ras突变模式，这与未暴露对照小鼠肺肿瘤中鉴定的突变模式不同。这些结果表明，K-ras基因的突变参与了BMP和TNM暴露后B6 C3 F1肺癌的发生，肺肿瘤中突变谱的高频率和特异性（G → A转换）可能是由于母体化合物或其代谢产物的体内遗传毒性。
Based on long-term toxicity and carcinogencity studies in B6C3F1 mice conducted by the National Toxicology Program, 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) and tetranitromethane (TNM) have been identified as carcinogens. Following 2 yr of exposure to 312, 625, or 1,250 ppm BMP in feed, or exposure to 0.5 or 2 ppm TNM by inhalation, increased incidences of lung neoplasms were observed in B6C3F1 mice at all exposure concentrations compared to unexposed mice. The present study characterizes genetic alterations in the K-rasprotooncogene in BMP- and TNM-induced lung neoplasms, respectively, and compares the findings to spontaneous lung neoplasms from corresponding control mice. The frequencies of the K-rasmutations were 57% (29/51) in BMP-induced lung neoplasms compared to 15% (3/20) in lung neoplasms from dosed feed control mice, and 54% (14/26) in TNM-induced lung neoplasms compared to 60% (3/5) in lung neoplasms from inhalation control mice. G → A transitions at the second base of the K-rascodon 12 (GGT → GAT) were the most frequent pattern of K-rasmutations identified in BMP-induced (20/29) and TNM-induced lung neoplasms (13/14), which differed from the mutational patterns identified in the lung neoplasms from unexposed control mice. These results indicate that mutations in the K-rasgene are involved in B6C3F1 lung carcinogenesis following BMP- and TNM-exposure, and the high frequency and specificity of therasmutation profile in lung neoplasms (G → A transition) may be due toin vivogenotoxicity by the parent compounds or their metabolites.