Van Benthem J, Wild C P, Vermeulen E, Den Engelse L, Scherer E
Division of Chemical Carcinogenesis, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), Amsterdam.
Carcinogenesis. 1991 Oct;12(10):1831-7. doi: 10.1093/carcin/12.10.1831.
The formation and short-term persistence of O6-methylguanine (O6-meGua) and 7-methylguanine (7-meGua) in individual cells of various target and non-target tissues for tumor induction in rats were examined after a single dose of N-nitroso-N-methylbenzylamine (NMBzA). In the principal target organ, the esophagus, both adducts were observed at 6 h after 0.5, 1.0 and 2.5 mg NMBzA/kg in a dose-dependent manner in nuclei of epithelial cells only. Nuclear staining in this organ had apparently declined by 72 h and modified nuclei were found in the more differentiated cells located closer to the lumen. In epithelial cells of the tongue, another target organ of NMBzA, methylation at 6 h was also dose dependent. At 72 h nuclear staining was lower and again largely located in differentiated cells. In the liver, a non-target organ, O6-meGua was not detectable and 7-meGua-specific staining was weak, being only observed at 6 h after the highest dose. Dose-dependent DNA methylation was seen, both at 6 and 72 h, in other non-target organs such as lung (bronchiolar epithelial cells), trachea (epithelial and glandular cells) and nasal cavity (respiratory epithelial cells, ductal cells of the respiratory lamina propria and cells of Bowman glands of the olfactory lamina propria); the nuclei of the glandular cells were highly methylated. Visual inspection of lung, trachea and nasal cavity indicated no or only minor losses of O6-meGua and 7-meGua between 6 and 72 h. Microdensitometric determination of the nuclear staining at 6 and 72 h indicated that the promutagenic O6-meGua was partially lost from cells of the tongue epithelium but did persist in esophageal epithelial cells; 7-meGua was lost to a substantial extent from both tongue and esophagus. The present results imply that the organotropism of NMBzA is not uniquely determined either by the initial level or the short-term persistence of DNA methylation.
在给大鼠单次注射N-亚硝基-N-甲基苄胺（NMBzA）后，检测了大鼠多种肿瘤诱发靶组织和非靶组织单个细胞中O6-甲基鸟嘌呤（O6-meGua）和7-甲基鸟嘌呤（7-meGua）的形成及短期持续性。在主要靶器官食管中，给予0.5、1.0和2.5mg NMBzA/kg后6小时，仅在上皮细胞核中以剂量依赖性方式观察到两种加合物。该器官的细胞核染色在72小时时明显下降，在更靠近管腔的分化程度更高的细胞中发现了修饰的细胞核。在NMBzA的另一个靶器官舌上皮细胞中，6小时时的甲基化也是剂量依赖性的。72小时时细胞核染色较低，且同样主要位于分化细胞中。在非靶器官肝脏中，未检测到O6-meGua，7-meGua特异性染色较弱，仅在最高剂量后6小时观察到。在其他非靶器官如肺（细支气管上皮细胞）、气管（上皮和腺细胞）和鼻腔（呼吸上皮细胞、呼吸固有层导管细胞和嗅固有层鲍曼腺细胞）中，6小时和72小时时均可见剂量依赖性DNA甲基化；腺细胞核高度甲基化。对肺、气管和鼻腔的肉眼观察表明，6至72小时之间O6-meGua和7-meGua没有损失或仅有少量损失。对6小时和72小时细胞核染色的显微密度测定表明，致突变性的O6-meGua在舌上皮细胞中部分丢失，但在食管上皮细胞中持续存在；7-meGua在舌和食管中均有大量丢失。目前的结果表明，NMBzA的器官亲和性并非由DNA甲基化的初始水平或短期持续性唯一决定。
