Ratko T A, Braun R J, Pezzuto J M, Beattie C W
Department of Pharmacology, University of Illinois School of Medicine, Chicago 60612.
Cancer Res. 1988 Jun 1;48(11):3090-3.
Virgin Sprague-Dawley rats exhibiting regular estrous cycles were used as a model system to determine whether the level of circulating estrogen modifies the alkylation pattern of mammary gland DNA by a direct-acting carcinogen, N-methyl-N-nitrosourea (NMU). The concentration of 7-methylguanine and O6-methylguanine were similar in mammary epithelial DNA 0.25, 0.50, and 1.0 h after i.v. injection of 50 mg/kg body weight NMU on different days of the rat estrous cycle. However, O6-methylguanine was significantly higher in mammary gland DNA 8 and 24 h after a single i.v. dose of carcinogen on proestrus or estrus, compared to rats receiving carcinogen on diestrus. There was no difference in the 7-methylguanine levels at 8 h in any group, but this adduct was higher in estrous-treated rats at 24 h. The ratio of O6-methylguanine to 7-methylguanine was significantly lower at 8 h in mammary gland DNA from diestrous-injected rats, and this difference reflected the lower level of O6-methylguanine adducts in this group. In contrast, O6-methylguanine concentrations in DNA extracted from the liver of the same animals were virtually identical at all time periods examined. 7-Methylguanine levels were higher in the liver at 0.5, 1, 8, and 24 h post-NMU in proestrus as compared with diestrous-injected rats. The observed adduct clearance suggests that rat mammary epithelium may contain repair systems capable of removing O6-methylguanine. These results also suggest that the initial removal of the O6-methylguanine lesions in mammary epithelial DNA (rather than the initial rate of alkylation) is affected by the hormonal environment during carcinogen exposure. This effect may be tissue specific since removal of O6-methylguanine from liver DNA is apparently not altered by the stage of the estrous cycle at which NMU is administered.
选用具有规律发情周期的处女斯普拉格-道利大鼠作为模型系统，以确定循环雌激素水平是否会改变直接作用致癌物N-甲基-N-亚硝基脲（NMU）对乳腺DNA的烷基化模式。在大鼠发情周期的不同日子，静脉注射50mg/kg体重的NMU后0.25、0.50和1.0小时，乳腺上皮DNA中7-甲基鸟嘌呤和O6-甲基鸟嘌呤的浓度相似。然而，与在动情后期接受致癌物注射的大鼠相比，在发情前期或发情期单次静脉注射致癌物后8小时和24小时，乳腺DNA中的O6-甲基鸟嘌呤显著更高。任何组在8小时时7-甲基鸟嘌呤水平均无差异，但在24小时时，发情期处理的大鼠中该加合物更高。在动情后期注射大鼠的乳腺DNA中，8小时时O6-甲基鸟嘌呤与7-甲基鸟嘌呤的比值显著更低，这种差异反映了该组中O6-甲基鸟嘌呤加合物水平更低。相比之下，在所有检查时间段，从同一动物肝脏中提取的DNA中的O6-甲基鸟嘌呤浓度几乎相同。与动情后期注射的大鼠相比，发情前期注射NMU后0.5、1、8和24小时肝脏中的7-甲基鸟嘌呤水平更高。观察到的加合物清除情况表明，大鼠乳腺上皮可能含有能够去除O6-甲基鸟嘌呤的修复系统。这些结果还表明，致癌物暴露期间的激素环境会影响乳腺上皮DNA中O6-甲基鸟嘌呤损伤的初始清除（而非初始烷基化速率）。这种效应可能具有组织特异性，因为从肝脏DNA中去除O6-甲基鸟嘌呤显然不会因给予NMU时的发情周期阶段而改变。
