PERSISTENCE OF O6-ETHYLGUANINE IN RAT-BRAIN DNA - CORRELATION WITH NERVOUS SYSTEM-SPECIFIC CARCINOGENESIS BY ETHYLNITROSOUREA
PERSISTENCE OF O6-ETHYLGUANINE IN RAT-BRAIN DNA - CORRELATION WITH NERVOUS SYSTEM-SPECIFIC CARCINOGENESIS BY ETHYLNITROSOUREA
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DOI：
10.1073/pnas.71.3.639
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发表时间：
1974-01-01
影响因子：
11.1
通讯作者：
RAJEWSKY, MF
中科院分区：
文献类型：
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作者：
GOTH, R;RAJEWSKY, MF
N-乙基-N-亚硝脲在围产期对大鼠的致癌作用的神经系统特异性是特别有趣的，因为最终反应物-亲电乙基阳离子的形成是非酶发生的，因此不是组织特异性的。确实，在靶组织(脑)和非靶组织(肝)的DNA中发现了类似的初始程度的DNA乙基化，在脉冲[1-14C]乙基亚硝脲1小时后，就O6-乙基鸟嘌呤、N7-乙基鸟嘌呤和N3-乙基腺嘌呤的摩尔分数而言。然而，在240小时的观察期内，O6-乙基鸟嘌呤(一种在DNA复制过程中可能导致异常碱基配对的修饰碱基)在大脑中的消除速度(半衰期约为220小时)显著低于肝脏(约30小时)，也远低于N7-乙基鸟嘌呤(约90小时)和N3-乙基腺嘌呤(约16小时)从脑DNA中的消除速度。这些数据表明，在乙基亚硝脲的肿瘤转化过程中，O6-乙基鸟嘌呤从DNA中的消除速度可能是一个重要的因素(与靶细胞的DNA复制有关)。
The nervous system specificity of the carcinogenic effect ofN-ethyl-N-nitrosourea in rats at the perinatal age is of particular interest because the formation of the ultimate reactant, an electrophilic ethyl cation, occurs nonenzymatically and, hence, is not tissue specific. Indeed, similar initial degrees of DNA ethylation were found in the DNA of target (brain) and nontarget tissue (liver), in terms of the molar fractions ofO6-ethylguanine,N7-ethylguanine, andN3-ethyladenine 1 hr after a pulse of [1-14C]ethylnitrosourea. However, over a 240-hr period of observation, the elimination rate from DNA ofO6-ethylguanine (a modified base likely to cause anomalous base pairing during DNA replication) was strikingly slower in brain (half-life, about 220 hr) as compared to liver (about 30 hr), and also much slower than the elimination rates from brain DNA ofN7-ethylguanine (about 90 hr) andN3-ethyladenine (about 16 hr). The data suggest that the rate of elimination from DNA ofO6-ethylguanine may be an important factor (with the requirement for DNA replication of the target cell) in neoplastic transformation by ethylnitrosourea.