Zimmermann F K, Gröschel-Stewart U, Scheel I, Resnick M A
Mutat Res. 1985 Jun-Jul;150(1-2):203-10. doi: 10.1016/0027-5107(85)90116-2.
Several aprotic polar solvents were shown to induce mitotic aneuploidy in yeast: diethyl ketone, gamma-valerolactone, pyridine, pivalinic acid nitrile, phenylacetonitrile and fumaric acid dinitrile. Only fumaric acid dinitrile also strongly induced other types of genetic effects including mitotic crossing-over, mitotic gene conversion and point mutation. The other substances only induced aneuploidy and this only over a very narrow dose range. The treatment protocol used suggested that these chemicals acted via interference with tubulin assembly and disassembly causing a malfunctioning of spindle fiber microtubules. This hypothesis was tested using twice recycled porcine brain tubulin. Diethyl ketone, gamma-valerolactone, pyridine and phenylacetonitrile inhibited GTP-promoted assembly of porcine brain tubulin in vitro in the concentration range needed for the induction of mitotic aneuploidy in yeast. Pivalinic acid nitrile accelerated tubulin aggregation whereas fumaric acid dinitrile had no effect even at concentrations 18 times higher than the lowest tested concentration effective in yeast. The in vitro experiments with porcine brain tubulin further suggest that genetic change can result from interference with specific protein-protein interactions. Fumaric acid dinitrile was the only exception since it did induce aneuploidy but had no effects on the assembly of porcine brain tubulin. This could be caused either by interference with protein-protein interactions other than between molecules during assembly and disassembly of microtubules or species-specific differences in susceptibility between yeast spindle and porcine brain tubulin.
二乙酮、γ-戊内酯、吡啶、新戊腈、苯乙腈和富马酸二腈。只有富马酸二腈还强烈诱导其他类型的遗传效应，包括有丝分裂交换、有丝分裂基因转换和点突变。其他物质仅诱导非整倍体，而且仅在非常窄的剂量范围内。所使用的处理方案表明，这些化学物质通过干扰微管蛋白的组装和拆卸起作用，导致纺锤体纤维微管功能失常。使用两次回收的猪脑微管蛋白对这一假设进行了测试。在诱导酵母有丝分裂非整倍体所需的浓度范围内，二乙酮、γ-戊内酯、吡啶和苯乙腈在体外抑制了猪脑微管蛋白的GTP促进组装。新戊腈加速了微管蛋白聚集，而富马酸二腈即使在比酵母中测试的最低有效浓度高18倍的浓度下也没有影响。用猪脑微管蛋白进行的体外实验进一步表明，遗传变化可能源于对特定蛋白质-蛋白质相互作用的干扰。富马酸二腈是唯一的例外，因为它确实诱导了非整倍体，但对猪脑微管蛋白的组装没有影响。这可能是由于在微管组装和拆卸过程中干扰了分子间以外的蛋白质-蛋白质相互作用，或者是由于酵母纺锤体和猪脑微管蛋白之间敏感性的物种特异性差异。
