Perocco P, Del Ciello C, Mazzullo M, Rocchi P, Ferreri A M, Paolini M, Pozzetti L, Cantelli-Forti G
Institute of Cancerology, University of Bologna, Italy.
Mutat Res. 1997 Nov 27;394(1-3):29-35. doi: 10.1016/s1383-5718(97)00120-4.
Cytotoxic and cell-transforming activities of methyl thiophanate a systemic fungicide capable of entering plant cells and thus controlling fungal diseases that have already started were studied in an in vitro medium-term (6-8 weeks) experimental model utilizing BALB/c 3T3 cells. Cells were exposed to the chemical, dissolved in dimethyl sulfoxide, in the absence or presence of an exogenous metabolizing system derived from rat livers supplemented with cofactors (S9 mix). In the absence of metabolic activation, methyl thiophanate exerted cytotoxic activity, evidenced through the formation of cell colonies, at low doses (> 10 micrograms/ml). However, the cytotoxic activity was greatly reduced by the S9 mix-induced metabolic activation of the chemical. Without bioactivation, cell-transforming potential, evidenced through the induction of transformation foci, was observable only at the highest (weakly toxic) dose employed (25 micrograms/ml). On the contrary, in the presence of metabolic activation, the cell-transforming activity was detectable at all tested doses (i.e. from 20 to 200 micrograms/ml) and it was particularly evident in a level-II transformation amplification test when the cells were allowed to perform active proliferative activity. These results, providing further information on the activity of methyl thiophanate in multistep carcinogenesis as possible genotoxic and/or co-carcinogenic agent, may contribute to better evaluate the oncogenic risk to man.
利用BALB/c 3T3细胞，在体外中期（6 - 8周）实验模型中研究了甲基托布津（一种能够进入植物细胞从而控制已发生的真菌病害的系统性杀菌剂）的细胞毒性和细胞转化活性。细胞在不存在或存在补充了辅因子的大鼠肝脏来源的外源性代谢系统（S9混合物）的情况下，暴露于溶解在二甲基亚砜中的该化学物质。在没有代谢活化的情况下，甲基托布津在低剂量（>10微克/毫升）时表现出细胞毒性活性，这通过细胞集落的形成得以证明。然而，S9混合物诱导的该化学物质的代谢活化大大降低了细胞毒性活性。在没有生物活化作用时，通过转化灶的诱导所证明的细胞转化潜能仅在所使用的最高（低毒）剂量（25微克/毫升）下可观察到。相反，在存在代谢活化的情况下，在所有测试剂量（即20至200微克/毫升）下均可检测到细胞转化活性，并且当细胞进行活跃增殖活动时，在二级转化扩增试验中这种活性尤为明显。这些结果为甲基托布津在多步骤致癌过程中作为可能的遗传毒性和/或促癌剂的活性提供了进一步信息，可能有助于更好地评估对人类的致癌风险。
