Ludeke B, Meier T, Kleihues P
Institute of Pathology, University of Zurich, Switzerland.
IARC Sci Publ. 1991(105):286-93.
Aliphatic methylalkylnitrosamines with a chain length of three to six carbon atoms are powerful oesophageal carcinogens in rats and have been shown to methylate target organ DNA preferentially. This class of carcinogens is efficiently metabolized not only in the oesophageal mucosa but also in the mucosa of the nasal and oral cavity, trachea and bronchioli, i.e., tissues derived from the rat ventral entoderm. In order to determine whether more than one cytochrome P450 isozyme is involved in the bioactivation of asymmetrical aliphatic dialkylnitrosamines in these tissues, we have studied the effects of various modulators of nitrosamine metabolism, including dietary zinc deficiency, ethanol and disulfiram, on DNA alkylation by N-nitrosomethyl-n-butylamine (NMBA) and its ethyl analogue N-nitrosoethyl-n-butylamine (NEBA). Formation of O6-methyl- and O6-ethyldeoxyguanosine by a single dose of NMBA and NEBA, respectively, was quantified after a survival time of 6 h by immuno-slot-blot assay. In control rats, methylation of DNA by NMBA was highest in oesophagus, followed by nasal mucosa, liver and lung. Formation of O6-ethyldeoxyguanosine from NEBA, however, was twice as high in liver as in nasal mucosa and lung and four times as high in liver as in oesophagus. In oesophagus, trachea and bronchioli, both nitrosamines were selectively metabolized in mucosal cells. Bioactivation of NMBA and NEBA was almost completely inhibited in nasal mucosa by ethanol. In contrast, a striking interorgan shift in DNA methylation by NMBA from liver (-50%) to lung (+100%), oesophagus (+300%) and nasal mucosa (+400%) was obtained with dietary disulfiram, whereas only 20-50% increases in extrahepatic DNA ethylation were determined for NEBA.(ABSTRACT TRUNCATED AT 250 WORDS)
碳链长度为三至六个碳原子的脂肪族甲基烷基亚硝胺是大鼠体内强大的食管致癌物，并且已被证明能优先使靶器官DNA甲基化。这类致癌物不仅在食管黏膜中能高效代谢，在鼻腔、口腔、气管和细支气管的黏膜中也能高效代谢，即来源于大鼠腹侧内胚层的组织。为了确定是否有不止一种细胞色素P450同工酶参与这些组织中不对称脂肪族二烷基亚硝胺的生物活化过程，我们研究了亚硝胺代谢的各种调节剂，包括饮食缺锌、乙醇和双硫仑，对N - 亚硝基甲基 - n - 丁胺（NMBA）及其乙基类似物N - 亚硝基乙基 - n - 丁胺（NEBA）引起的DNA烷基化的影响。在6小时的存活时间后，通过免疫斑点印迹法对单次给予NMBA和NEBA分别形成的O6 - 甲基 - 和O6 - 乙基脱氧鸟苷进行定量。在对照大鼠中，NMBA引起的DNA甲基化在食管中最高，其次是鼻黏膜、肝脏和肺。然而，NEBA形成的O6 - 乙基脱氧鸟苷在肝脏中的含量是鼻黏膜和肺中的两倍，是食管中的四倍。在食管、气管和细支气管中，两种亚硝胺都在黏膜细胞中被选择性代谢。乙醇几乎完全抑制了鼻黏膜中NMBA和NEBA的生物活化。相反，饮食中加入双硫仑后，NMBA引起的DNA甲基化在肝脏中减少了50%，而在肺中增加了100%、食管中增加了300%、鼻黏膜中增加了400%，而对于NEBA，肝外DNA乙基化仅增加了20 - 50%。（摘要截取自250字）
