Albertini S, Gocke E
Department of Toxicology F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Mutat Res. 1993 Feb;298(4):237-46. doi: 10.1016/0165-1218(93)90002-u.
An increase in the number of mutant colonies in the Ames test is generally taken as a strong indication for a genotoxic (e.g., DNA damaging) property of the test compound or its metabolites. However, a few examples are known in which mechanisms usually related to some sort of growth enhancement will lead to increases in mutant frequencies of spontaneous origin. The renin inhibitor Ro 42-5892 increased the number of mutant colonies of strain TA1538 and to a lesser degree of TA98 in the standard plate incorporation assay (Ames test). Since there is no chemical basis for a 'DNA reactivity' of this compound, experiments were performed to obtain information about possible indirect mechanisms of enhancing the number of spontaneous mutant colonies. Circumstantial evidence is presented to attribute the weak activity not to an inherent genotoxic property but rather to an as yet undefined indirect effect on the expression of spontaneous mutants. Since Ro 42-5892 contains a histidine residue it was a reasonable assumption to suspect a growth enhancing property of the test compound. However, none of the strains showed an elevation of the number of revertant colonies or an increase in the density of the background growth. In addition, structurally related non-histidine containing renin inhibitors showed absolutely no increase in the number of revertant colonies. Furthermore, no growth induction (either in liquid or under selective conditions) and no histidine cleave off by a TA1538/TA98 specific metabolism could be shown. A second line of evidence showing parallelism to growth enhancing compounds concerns the comutagenicity of histidine containing renin inhibitors. When Ro 42-5892 was tested in combination with established mutagens, a multiplicative synergism was found. This effect was observed not only in strains TA1538 and TA98 but also in the standard Salmonella tester strains where the spontaneous mutant frequency was not increased by Ro 42-5892. Analogous effects were previously shown for free histidine, isohistidine, phenobarbital and tetracycline and in part explained by molecular mechanisms.
在艾姆斯试验中，突变菌落数量的增加通常被视为受试化合物或其代谢产物具有遗传毒性（如DNA损伤）特性的有力指征。然而，已知有一些例子，其中通常与某种生长增强相关的机制会导致自发产生的突变频率增加。在标准平板掺入试验（艾姆斯试验）中，肾素抑制剂Ro 42 - 5892增加了TA1538菌株的突变菌落数量，对TA98菌株的影响较小。由于该化合物不存在“DNA反应性”的化学基础，因此进行了实验以获取有关增加自发突变菌落数量的可能间接机制的信息。有间接证据表明，这种微弱活性并非源于内在的遗传毒性特性，而是对自发突变体表达产生了尚未明确的间接影响。由于Ro 42 - 5892含有组氨酸残基，因此合理推测受试化合物具有生长增强特性。然而，没有一个菌株的回复菌落数量增加或背景生长密度增大。此外，结构相关的不含组氨酸的肾素抑制剂的回复菌落数量绝对没有增加。此外，未显示出（在液体中或选择性条件下的）生长诱导作用，也未发现TA1538/TA98特异性代谢可裂解组氨酸。显示与生长增强化合物具有相似性的第二条证据涉及含组氨酸的肾素抑制剂的共诱变作用。当Ro 42 - 5892与已确定的诱变剂联合测试时，发现了倍增协同作用。不仅在TA1538和TA98菌株中观察到了这种效应，在标准沙门氏菌测试菌株中也观察到了，而Ro 42 - 5892并未增加这些菌株的自发突变频率。以前对游离组氨酸、异组氨酸、苯巴比妥和四环素也显示出类似效应，部分原因已通过分子机制得到解释。
