Yamada Y, Weller R O, Kleihues P, Ludeke B I
Department of Pathology, University Hospital, Zürich, Switzerland.
Carcinogenesis. 1992 Jul;13(7):1171-5. doi: 10.1093/carcin/13.7.1171.
Consumption of alcoholic beverages has been identified as a major cause of oesophageal cancer in industrialized countries, with an exceptionally high risk associated with apple-based liquors (calvados). In the present study, we have determined the dose--activity relationship of the effects of coincident ethanol on the formation of O6-methyldeoxyguanosine (O6-MEdG) by the oesophageal carcinogen N-nitrosomethylbenzylamine (NMBzA). Male Fischer 344 rats received a single intragastric dose of NMBzA (2.5 mg/kg body wt; 7.4 ml/kg body wt) in tap water containing 0-20% ethanol (v/v). Survival time was 3 h. In controls, concentrations of O6-MEdG were similar in oesophagus, lung and liver (11-14.9 mumol/mol dG). In oesophagus, coincident ethanol increased levels of O6-MEdG from 15.2 mumol/mol (0.1% ethanol) to 46.0 mumol/mol (20%). This increase was dose dependent for 1-20% ethanol; however, low doses produced a larger effect per gram of ethanol than higher doses. In lung, concentrations of O6-MEdG increased from 11 mumol/mol (0.1%) to a plateau value of 24 mumol/mol (greater than or equal to 5%). In nasal mucosa, an increase in O6-MEdG from 3.9 mumol/mol (controls) to 30.7 mumol/mol was observed with 4% ethanol. Effects of ethanol on hepatic DNA methylation were statistically non-significant. Modulation of NMBzA bioactivation by various alcoholic beverages (adjusted to 4% ethanol) was also investigated. Increases in oesophageal O6-MEdG were similar (+50% to +116%) with pear brandy, rice wine (sake), farm-made calvados, gin, Scotch whisky, white wine, Pilsner beer and aqueous ethanol. Significantly higher increases were elicited by commercially distilled calvados (+125%) and red burgundy (+162%). In contrast to its effects at an ethanol content of 4%, farm-made calvados diluted to 20% ethanol produced significantly higher (+200%) increases in oesophageal DNA methylation than aqueous ethanol (+148%). Our results show that ethanol is an effective modulator of nitrosamine bioactivation in vivo at intake levels equivalent to moderate social drinking, and that some alcoholic beverages contain congeners that amplify the effects of ethanol, suggesting that modulation of nitrosamine metabolism by acute ethanol may play a role in the etiology of human cancer.
在工业化国家，酒精饮料的消费已被确认为食管癌的主要病因，苹果酒（卡尔瓦多斯）相关风险异常高。在本研究中，我们确定了同时摄入乙醇对食管致癌物N - 亚硝基甲基苄胺（NMBzA）诱导形成O6 - 甲基脱氧鸟苷（O6 - MEdG）影响的剂量 - 活性关系。雄性Fischer 344大鼠在含0 - 20%乙醇（v/v）的自来水中接受单次胃内注射NMBzA（2.5 mg/kg体重；7.4 ml/kg体重）。存活时间为3小时。在对照组中，食管、肺和肝脏中O6 - MEdG的浓度相似（11 - 14.9 μmol/mol dG）。在食管中，同时摄入乙醇使O6 - MEdG水平从15.2 μmol/mol（0.1%乙醇）增加到46.0 μmol/mol（20%）。对于1 - 20%的乙醇，这种增加呈剂量依赖性；然而，低剂量每克乙醇产生的效应比高剂量更大。在肺中，O6 - MEdG浓度从11 μmol/mol（0.1%）增加到稳定值24 μmol/mol（≥5%）。在鼻黏膜中，观察到4%乙醇使O6 - MEdG从3.9 μmol/mol（对照组）增加到30.7 μmol/mol。乙醇对肝脏DNA甲基化的影响在统计学上无显著意义。我们还研究了各种酒精饮料（调整至4%乙醇）对NMBzA生物活化的调节作用。梨白兰地、米酒（清酒）、自制卡尔瓦多斯、杜松子酒、苏格兰威士忌、白葡萄酒、比尔森啤酒和含水乙醇使食管中O6 - MEdG增加相似（+50%至+116%）。商业蒸馏卡尔瓦多斯（+125%）和勃艮第红葡萄酒（+162%）引起的增加明显更高。与4%乙醇含量时的作用相反，稀释至20%乙醇的自制卡尔瓦多斯使食管DNA甲基化增加显著高于含水乙醇（+200%对+148%）。我们的结果表明，在相当于适度社交饮酒的摄入水平下，乙醇是体内亚硝胺生物活化的有效调节剂，并且一些酒精饮料含有能放大乙醇作用的同系物，这表明急性乙醇对亚硝胺代谢的调节可能在人类癌症病因学中起作用。
