Sgambato A, Iavicoli I, De Paola B, Bianchino G, Boninsegna A, Bergamaschi A, Pietroiusti A, Cittadini A
Institute of General Pathology, "Giovanni XXIII" Cancer Research Center, Catholic University of Sacred Heart, Rome, Italy.
Toxicol Ind Health. 2009 Mar;25(2):141-51. doi: 10.1177/0748233709104867.
Methyl tertiary butyl ether (MTBE) is the most widely used motor vehicle fuel oxygenate since it reduces harmful emissions due to gasoline combustion. However, the significant increase in its use in recent years has raised new questions related to its potential toxicity. In fact, although available data are somehow conflicting, there is evidence that MTBE is a toxic substance that may have harmful effects on both animals and humans and an unresolved problem is the role played by MTBE metabolites, especially tertiary butyl alcohol (TBA), in determining toxic effects due to MTBE exposure. In this study, the toxic effects of MTBE have been analyzed on a normal diploid rat fibroblast cell line (Rat-1) and compared to the effects of TBA. The results obtained suggest that both MTBE and TBA inhibit cell growth in vitro but with different mechanisms in terms of effects on the cell cycle progression and on the modulation of cell cycle regulatory proteins. In fact, MTBE caused an accumulation of cells in the S-phase of the cell cycle, whereas TBA caused an accumulation in the G0/G1-phase with different effects on the expression of cyclin D1, p27Kip1, and p53. Moreover, both MTBE and TBA were also shown to induce DNA damage, as assessed in terms of oxidative DNA damage and nuclear DNA fragmentation, that appeared to be susceptible of repair by the cell DNA-repair machinery. In conclusion, these findings suggest that both MTBE and TBA can exert, by acting through different molecular mechanisms, important biological effects on fibroblasts in vitro. Further studies are warranted to shed light on the mechanisms responsible for the observed effects and on their potential significance for the in-vivo exposure.
甲基叔丁基醚（MTBE）是使用最广泛的机动车燃料含氧化合物，因为它能减少汽油燃烧产生的有害排放物。然而，近年来其使用量的显著增加引发了与潜在毒性相关的新问题。事实上，尽管现有数据存在一定冲突，但有证据表明MTBE是一种有毒物质，可能对动物和人类都有有害影响，而一个尚未解决的问题是MTBE代谢产物，尤其是叔丁醇（TBA），在MTBE暴露所致毒性效应中所起的作用。在本研究中，分析了MTBE对正常二倍体大鼠成纤维细胞系（Rat-1）的毒性作用，并与TBA的作用进行了比较。所得结果表明，MTBE和TBA在体外均抑制细胞生长，但在对细胞周期进程和细胞周期调节蛋白的调节方面机制不同。实际上，MTBE导致细胞在细胞周期的S期积累，而TBA导致细胞在G0/G1期积累，对细胞周期蛋白D1、p27Kip1和p53的表达有不同影响。此外，MTBE和TBA还均被证明可诱导DNA损伤，从氧化性DNA损伤和核DNA片段化方面评估，这种损伤似乎可被细胞DNA修复机制修复。总之，这些发现表明MTBE和TBA均可通过不同分子机制对体外成纤维细胞产生重要生物学效应。有必要进一步开展研究，以阐明导致所观察到效应的机制及其在体内暴露中的潜在意义。
