Jurado J, Pueyo C
Departamento de Bioquímica y Biología Molecular, Universidad de Córdoba, Spain.
Environ Mol Mutagen. 1995;26(1):86-93. doi: 10.1002/em.2850260113.
This study investigates the mutagenicity of nifurtimox (NFX) and eight analogues in Salmonella typhimurium indicator strains that possess different levels of classical nitroreductase or O-acetyltransferase activities. The NFX analogues tested replace the 3-methyl-4-yl-tetrahydro-1,4-thiazine-1,1-dioxide group of the parent compound with the following other groups: indazol-1-yl (1G); pyrazol-1-yl (1B); benzimidazol-1-yl (1E); 1,2,4-triazol-4-yl (1D); 1-methyl-3-methylthio-1,2,4-triazol-4-yl-5-thione (1I); 3,5-bis(methylthio)-1,2,4-triazol-4-yl (1H); 1-adamantyl (ADA); and 4,6-diphenylpyridin-1-yl-2-one (1K). In the genetic backgrounds of the standard Ames tester strains TA98 and TA100, these bacteria combine the L-arabinose resistance forward mutation assay (Ara test) with a deficiency or overproduction of either nitroreduction or O-acetylation. The Ara test revealed, in agreement with previous findings, important differences between TA98 and TA100 and demonstrated, moreover, that these genetic differences are of significance in mutagenicity testing with nitrofuran compounds. The Ara test also indicated dissimilarities between the metabolic activation of NFX and its analogues, these compounds being classified in three different groups according to their mutagenicity toward strain BA14 (genetic background of TA98) and its derivatives. The first group included analogues (1G, 1E, 1I, and ADA) that showed similar mutagenic potency in all bacterial strains. These compounds are considered not to be substrates for both classical nitroreductase and O-acetyltransferase. The second group included compounds (analogues 1B and 1K, and the reference drug NFX) with increased mutagenicity toward the strain overproducing the classical nitroreductase, and/or reduced mutagenicity toward the corresponding deficient bacteria. These compounds are considered to be activated by the classical nitroreductase. The third group (analogues 1D and 1H) was activated by bacterial O-acetyltransferase, and consequently showed increased and decreased mutagenicity with the particular overproducer or deficient bacterial strain, as compared to their isogenic parentals. Previous reports have pointed out interest in NFX analogue 1H as a promising candidate for the replacement of NFX. The present study further enhances the putative interest of compound 1H, based on the different metabolic activation pathway exhibited by this analogue as compared to the parental drug, NFX.
本研究调查了硝呋替莫（NFX）及其八种类似物在具有不同水平经典硝基还原酶或O - 乙酰转移酶活性的鼠伤寒沙门氏菌指示菌株中的致突变性。所测试的NFX类似物用以下其他基团取代了母体化合物的3 - 甲基 - 4 - 基 - 四氢 - 1,4 - 噻嗪 - 1,1 - 二氧化物基团：吲唑 - 1 - 基（1G）；吡唑 - 1 - 基（1B）；苯并咪唑 - 1 - 基（1E）；1,2,4 - 三唑 - 4 - 基（1D）；1 - 甲基 - 3 - 甲硫基 - 1,2,4 - 三唑 - 4 - 基 - 5 - 硫酮（1I）；3,5 - 双（甲硫基） - 1,2,4 - 三唑 - 4 - 基（1H）；1 - 金刚烷基（ADA）；以及4,6 - 二苯基吡啶 - 1 - 基 - 2 - 酮（1K）。在标准艾姆斯试验菌株TA98和TA100的遗传背景中，这些细菌将L - 阿拉伯糖抗性正向突变试验（Ara试验）与硝基还原或O - 乙酰化的缺陷或过量表达相结合。Ara试验与先前的研究结果一致，揭示了TA98和TA100之间的重要差异，并且还表明这些遗传差异在呋喃类化合物的致突变性测试中具有重要意义。Ara试验还表明了NFX及其类似物代谢活化之间的差异，这些化合物根据它们对菌株BA14（TA98的遗传背景）及其衍生物的致突变性被分为三个不同的组。第一组包括在所有细菌菌株中显示出相似致突变效力的类似物（1G、1E、1I和ADA）。这些化合物被认为不是经典硝基还原酶和O - 乙酰转移酶的底物。第二组包括对过量表达经典硝基还原酶的菌株致突变性增加和/或对相应缺陷细菌致突变性降低的化合物（类似物1B和1K以及参考药物NFX）。这些化合物被认为是由经典硝基还原酶激活的。第三组（类似物1D和1H）由细菌O - 乙酰转移酶激活，因此与它们的同基因亲本相比，在特定的过量生产者或缺陷细菌菌株中显示出增加和降低的致突变性。先前的报告指出对NFX类似物1H作为替代NFX的有希望的候选物感兴趣。本研究基于该类似物与母体药物NFX相比表现出的不同代谢活化途径，进一步增强了化合物1H的假定吸引力。
