Glatt H, de Balle L, Oesch F
Carcinogenesis. 1981;2(10):1057-61. doi: 10.1093/carcin/2.10.1057.
The activation of dimethylnitrosamine (DMN) to a bacterial mutagen in liver subcellular fraction and in intrasanguinous host-mediated assays was studied, in particular the effect of pretreatment of the animals with ethanol or acetone. Salmonella typhimurium TA 92 was much more sensitive to DMN mutagenicity than TA 100 and TA 1535 or Escherichia coli WP2uvrA and was used for the main part of the study. Noteworthy, in part already known, features of the in vitro activation are the relatively low pH optimum (pH 6-6.4), the non-linear dose-mutagenic response-relationship and the relatively high doses of DMN required for activation with control preparations. Pretreatment of mice with ethanol or acetone greatly reduced the minimal mutagenically effective concentration of DMN in the in vitro assay. Pretreatment with Aroclor 1254, an inducer frequently used in mutagenicity research, showed little effect when used alone, but reduced the potentiation by acetone. The results of the host-mediated assays substantially differed from those of the in vitro activation assays (a) in the relatively low dose of DMN required for mutagenicity to occur and (b) in the lack of potentiation by acetone-or ethanol-pretreatment. Acetone even led to a marginal decrease in mutagenicity. As a possible explantation for this apparent discrepancy were assume that with the in vitro system the activity of the dilute metabolizing system is limiting for the activation of DMN and induction therefore will increase the mutagenicity, whereas in vivo DMN is quantitatively metabolized in both induced and non-induced animals. The results show that caution has to be taken in the interpretation from in vitro results to the in vivo situation. In particular our in vivo experiments do not support the hypothesis that the induction by ethanol of an activating system with a low Km (which would strongly activate traces of DMN ingested with many foods) is one of the reasons for the increased risk of liver tumors in alcoholics.
研究了二甲基亚硝胺（DMN）在肝脏亚细胞组分和体内宿主介导试验中被激活为细菌诱变剂的情况，特别是用乙醇或丙酮对动物进行预处理的效果。鼠伤寒沙门氏菌TA 92对DMN诱变性的敏感性比TA 100、TA 1535或大肠杆菌WP2uvrA高得多，并用于该研究的主要部分。值得注意的是，部分已知的体外激活特征包括相对较低的最适pH值（pH 6 - 6.4）、非线性剂量-诱变反应关系以及用对照制剂激活所需的相对高剂量的DMN。用乙醇或丙酮对小鼠进行预处理大大降低了体外试验中DMN的最小诱变有效浓度。用艾氏剂1254（一种在诱变性研究中常用的诱导剂）进行预处理，单独使用时效果甚微，但可降低丙酮的增效作用。宿主介导试验的结果与体外激活试验的结果在以下方面有很大不同：（a）发生诱变性所需的DMN剂量相对较低；（b）丙酮或乙醇预处理缺乏增效作用。丙酮甚至导致诱变性略有下降。对于这种明显差异的一种可能解释是，在体外系统中，稀释代谢系统的活性限制了DMN的激活，因此诱导会增加诱变性，而在体内，DMN在诱导和未诱导的动物中都进行了定量代谢。结果表明，从体外结果推断体内情况时必须谨慎。特别是我们的体内实验不支持以下假设：乙醇诱导具有低Km的激活系统（这将强烈激活许多食物中摄入的微量DMN）是酗酒者肝脏肿瘤风险增加的原因之一。
