von Hofe E, Schmerold I, Nims R W, Keefer L K, Reist E J, Kleihues P
Laboratory of Neuropathology, University of Zürich, Switzerland.
Carcinogenesis. 1991 Apr;12(4):545-9. doi: 10.1093/carcin/12.4.545.
While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its beta-trideuterated derivative, N-nitroso( [2-D3]ethyl)methylamine (NEMA-d3), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14C]- and [1-ethyl-14C]-labeled NEMA-d3 were administered to adult male Fischer 344 rats as a single i.p. dose (0.05 mmol/kg; 4 h survival). Levels of methylated and ethylated purines in the DNA of various organs were determined by radio-chromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-methylguanine levels were found to be reduced by approximately 30% in liver and kidney, but were 160% greater in esophagus. This resulted in a decrease in the 7-methylguanine ratio for liver/esophagus from 109 to 29. O6-Methylguanine was diminished in liver and kidney, but levels in lung and esophagus were too low for quantitative detection. Similarly, deuteration led to an 18% decrease of 7-ethylguanine in hepatic DNA. The observed increase in esophageal DNA methylation correlates with the increased carcinogenicity of NEMA-d3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that beta-trideuteration of NEMA does not alter its bioavailability, the data suggest that the observed shift in target organ results from isotopically-induced changes in the balance among competing metabolic pathways in different rat tissues.
虽然N-亚硝基乙甲胺（NEMA）主要对肝脏具有致癌性，但其β-三重氘代衍生物N-亚硝基（[2-D3]乙基）甲胺（NEMA-d3）在食管中也会产生高肿瘤发生率。为了确定这种器官特异性的转变是否与DNA烷基化模式的改变有关，将[甲基-14C] - 和[1-乙基-14C] - 标记的NEMA-d3以单次腹腔注射剂量（0.05 mmol/kg；存活4小时）给予成年雄性Fischer 344大鼠。通过在Sephasorb-HP柱上进行放射性色谱法测定各器官DNA中甲基化和乙基化嘌呤的水平。与先前使用未氘代NEMA的数据相比，发现肝脏和肾脏中的7-甲基鸟嘌呤水平降低了约30%，但食管中的水平高160%。这导致肝脏/食管的7-甲基鸟嘌呤比率从109降至29。O6-甲基鸟嘌呤在肝脏和肾脏中减少，但肺和食管中的水平过低无法进行定量检测。同样，氘代导致肝脏DNA中7-乙基鸟嘌呤减少18%。观察到的食管DNA甲基化增加与NEMA-d3相对于该器官中未氘代NEMA的致癌性增加相关。由于药代动力学研究表明NEMA的β-三重氘代不会改变其生物利用度，数据表明观察到的靶器官转变是由不同大鼠组织中竞争代谢途径之间平衡的同位素诱导变化引起的。
