Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mutagenesis. 2010 May;25(3):257-69. doi: 10.1093/mutage/geq002. Epub 2010 Jan 31.
Diphenyl ditelluride (DPDT) is a potential prototype for the development of novel biologically active molecules. Thus, it is important to evaluate the toxic effects of this compound. In the present study, we evaluated the cytotoxic, genotoxic and mutagenic properties of DPDT in Chinese hamster fibroblast (V79) cells, in strains of the yeast Saccharomyces cerevisiae both proficient and deficient in several DNA repair pathways and in Salmonella typhimurium. DPDT induced frameshift mutations in both S.typhimurium and a haploid wild-type strain of S.cerevisiae. Mutants of S.cerevisiae defective in base excision repair and recombinational repair were more sensitive to DPDT. The results of a lactate dehydrogenase leakage assay suggest that DPDT is cytotoxic to V79 cells. At cytotoxic concentrations, this compound increased thiobarbituric reactive species levels and decreased the glutathione:GSSH ratio in yeast and V79 cells. DPDT generated single- and double-strand DNA breaks in V79 cells, both with and without metabolic activation, as revealed by alkaline and neutral comet assays. Moreover, an induction of oxidative DNA base damage was indicated by a modified comet assay using formamidopyrimidine DNA glycosylase and endonuclease III. Treatment with DPDT also induced micronucleus formation in V79 cells. Pre-incubation with N-acetylcysteine reduced DPDT's oxidative, genotoxic and mutagenic effects in yeast and V79 cells. Our results suggest that the toxic and mutagenic properties of DPDT may stem from its ability to disturb the redox balance of the cell, which leads to oxidative stress and the induction of DNA damage.
二苯并二碲（DPDT）是开发新型生物活性分子的潜在原型。因此，评估该化合物的毒性作用非常重要。在本研究中，我们评估了 DPDT 在中华仓鼠肺成纤维细胞（V79）细胞中的细胞毒性、遗传毒性和致突变性，以及在几种 DNA 修复途径均有缺陷的酵母 Saccharomyces cerevisiae 菌株和鼠伤寒沙门氏菌中的作用。DPDT 在鼠伤寒沙门氏菌和酿酒酵母的一个单倍体野生型菌株中均诱导移码突变。在碱基切除修复和重组修复均有缺陷的酿酒酵母突变体中，DPDT 更为敏感。乳酸脱氢酶渗漏测定的结果表明，DPDT 对 V79 细胞具有细胞毒性。在细胞毒性浓度下，该化合物增加了硫代巴比妥酸反应性物质的水平，并降低了酵母和 V79 细胞中的谷胱甘肽：GSSH 比值。DPDT 在 V79 细胞中产生单链和双链 DNA 断裂，无论是否有代谢激活，均通过碱性和中性彗星试验证实。此外，使用形式嘧啶 DNA 糖苷酶和内切核酸酶 III 的改良彗星试验表明，氧化 DNA 碱基损伤得到了诱导。DPDT 处理还诱导了 V79 细胞中的微核形成。用 N-乙酰半胱氨酸预先孵育可降低 DPDT 在酵母和 V79 细胞中的氧化、遗传毒性和致突变作用。我们的结果表明，DPDT 的毒性和致突变特性可能源于其扰乱细胞氧化还原平衡的能力，这导致了氧化应激和 DNA 损伤的诱导。
