Vogel E, Natarajan A T
Mutat Res. 1979 Aug;62(1):51-100. doi: 10.1016/0027-5107(79)90223-9.
The relationship in Drosophila males between chemical reaction pattern of mono-functional alkylating agents (AA), described in terms of primary alkylation pattern with DNA and proteins as well as the Swain--Scott s factor, and their biological effectiveness were investigated. The agents chosen for comparative analysis were the nitrosamides ENU and MNU, the methanesulfonic esters iPMS, EMS and MMS, the dialkylsulfate DMS, and the nitrosamines DEN and DMN. Parameters of their biological activity were mortality (LC50) of treated adult males, induction in post-meiotic stages of X-chromosomal recessive lethal mutations and 2--3 translocations after either adult feeding or injection. Induced frequencies of recessive lethals, determined for each AA with a range of concentrations, served as biological dosimeter for interaction with target DNA in the germ line. The results are interpreted as indicating for these AA a causal connection between the pattern of primary alkylation of DNA and the quality of genetic damage observed. 1. The agent with the lowest s value, ENU, and its pendant DEN, failed to produce translocations at mutation frequencies that reached 44% for ENU. The highest chromosome-breaking activity was attributed to AA with high s, MMS and DMS. For MMS, the proportions of translocations (T) to mutations (M) approximately reached a 1 : 1 ratio in stored spermatozoa, at a recessive-lethal frequency of 14%. Ability to break chromosomes, as indicated by the T : M ratios, decreased in the sequence MMS greater than or equal to DMS, MNU greater than DMN greater than EMS greater than iPMS greater than ENU = DEN. 2. Nearly the reversed sequence in relative mutagenci effectivenss was obtained when the (directly acting) AA were arranged on the basis of their CM4/LC50 ratios (CM4, the exposure condition producing 4% recessive lethals after injection): ENU greater than EMS greater than iPMS, MNU greater than MMS = DMS. 3. Among the AA, EMS had a somewhat unique position, in that it was slightly less effective in the translocation test, and also less cytotoxic but more mutagenic in the recessive-lethal test than one would expect from its s value. This is taken as an indication of the influence on biological effectiveness of factors other than the s value, e.g. methylation versus ethylation and the lipid/water partition ratio. An example of the latter was also provided by DMS which, although having the same s as MMS, with its 5-fold higher lipid/water partition ratio, was more toxic than MMS. 4. For those AA that were clearly active in the translocation tests--MMS, DMS, MNU, DMN and EMS--delayed formation of exchanges was observed. Only in 17 out of 555 translocation tests with positive response translocations were already found in progeny from unstored spermatozoa. Consequently, it was concluded that performance of storage experiments in Drosophila is an absolute necessity for the detection of this type of rearrangement by AA. 5...
研究了果蝇雄性体内单功能烷基化剂（AA）的化学反应模式（以与DNA和蛋白质的一级烷基化模式以及斯温-斯科特s因子来描述）与其生物学效应之间的关系。用于比较分析的试剂有亚硝基酰胺ENU和MNU、甲磺酸酯iPMS、EMS和MMS、硫酸二乙酯DMS以及亚硝胺DEN和DMN。其生物学活性参数包括经处理的成年雄性果蝇的死亡率（LC50）、减数分裂后阶段X染色体隐性致死突变的诱导率以及成年果蝇取食或注射后2至3次易位的诱导率。针对每种AA在一系列浓度下测定的隐性致死诱导频率，用作与生殖系中靶DNA相互作用的生物学剂量计。结果被解释为表明这些AA在DNA一级烷基化模式与所观察到的遗传损伤质量之间存在因果关系。1. s值最低的试剂ENU及其同类物DEN，在突变频率达到ENU的44%时未能产生易位。最高的染色体断裂活性归因于s值高的AA，即MMS和DMS。对于MMS，在储存精子中，易位（T）与突变（M）的比例在隐性致死频率为14%时约达到1 : 1。由T : M比值表明的染色体断裂能力按MMS≥DMS、MNU＞DMN＞EMS＞iPMS＞ENU = DEN的顺序降低。2. 当根据（直接作用的）AA的CM4/LC50比值（CM4，注射后产生4%隐性致死的暴露条件）对其进行排列时，得到了几乎相反的相对诱变效力顺序：ENU＞EMS＞iPMS、MNU＞MMS = DMS。3. 在AA中，EMS具有 somewhat独特的地位，即它在易位试验中的效果略差，并且在隐性致死试验中比根据其s值预期的细胞毒性更小但诱变作用更强。这被视为表明除s值之外的其他因素对生物学效应有影响，例如甲基化与乙基化以及脂/水分配比。DMS也提供了后者的一个例子，尽管它与MMS具有相同的s值，但其脂/水分配比高5倍，毒性比MMS更大。4. 对于那些在易位试验中明显有活性的AA——MMS、DMS、MNU、DMN和EMS——观察到交换的延迟形成。在555次有阳性反应的易位试验中，只有17次在未储存精子的后代中已经发现了易位。因此，得出结论，在果蝇中进行储存实验对于通过AA检测这种类型的重排是绝对必要的。5...
