Lamy Evelyn, Crössmann Catharina, Saeed Adal, Schreiner Peter R, Kotke Mike, Mersch-Sundermann Volker
Department of Environmental Health Sciences, University Medical Center Freiburg, Breisacher Strasse 115b, Freiburg 79106, Germany.
Environ Mol Mutagen. 2009 Apr;50(3):164-70. doi: 10.1002/em.20470.
In this study, we used the single cell gel electrophoresis (SCGE) assay and the micronucleus (MN) test to investigate the DNA damaging effects and the antigenotoxic potencies of three structurally related ITCs in human HepG2 cells. The results show that all three ITCs possess the characteristic of a "Janus" compound, i.e., they exert both significant genotoxicity and antigenotoxicity, depending on the concentrations used in the test systems applied. Regression line analysis of the results derived by SCGE analysis showed genotoxic potency of the ITCs in the following order: 3-methylthiopropyl ITC (MTPITC) > 4-methylthiobutyl ITC (MTBITC) > 5-methylthiopentyl ITC (MTPeITC); however, this order in genotoxic potency was not confirmed by MN analysis. Additionally, the MN test showed significant mutagenicity of the test substances at higher concentrations when compared with the SCGE assay. Twenty-four hour-treatment of the cells with the ITCs, followed by a 1-hr recovery period, showed significant DNA repair in the SCGE assay at a concentration > or =10 microM MTPITC, > or =3 microM MTBITC, and > or =0.1 microM MTPeITC, respectively. In antigenotoxicity studies, the most effective concentration of MTPITC and MTPeITC toward B(a)P-induced DNA damage was 0.1 muM in both test systems. MTBITC suppressed MN formation in B(a)P-treated cells to the background level at a concentration of 1 muM. The ambivalent character of the ITCs under studymust be further clarified, especially in the possiblecontext of high dose therapeutic applications.
在本研究中，我们使用单细胞凝胶电泳（SCGE）试验和微核（MN）试验，来研究三种结构相关的异硫氰酸酯（ITC）对人肝癌细胞系HepG2细胞的DNA损伤作用和抗遗传毒性潜力。结果表明，所有三种ITC都具有“两面神”化合物的特征，即根据测试系统中所使用的浓度，它们既表现出显著的遗传毒性，又表现出抗遗传毒性。对SCGE分析所得结果进行的回归线分析表明，ITC的遗传毒性潜力顺序如下：3-甲基硫代丙基异硫氰酸酯（MTPITC）＞4-甲基硫代丁基异硫氰酸酯（MTBITC）＞5-甲基硫代戊基异硫氰酸酯（MTPeITC）；然而，MN分析并未证实这种遗传毒性潜力顺序。此外，与SCGE试验相比，MN试验显示测试物质在较高浓度时具有显著的致突变性。用ITC对细胞进行24小时处理，随后有1小时的恢复期，结果显示，在SCGE试验中，分别在浓度≥10μM MTPITC、≥3μM MTBITC和≥0.1μM MTPeITC时，有显著的DNA修复。在抗遗传毒性研究中，在两个测试系统中，MTPITC和MTPeITC对苯并[a]芘诱导的DNA损伤最有效的浓度均为0.1μM。MTBITC在浓度为1μM时可将苯并[a]芘处理细胞中的MN形成抑制到背景水平。所研究的ITC的这种矛盾特性必须进一步阐明，特别是在高剂量治疗应用的可能背景下。
