Kassie F, Knasmüller S
Institute of Cancer Research, Borsckegasse 8A, A-1090, Vienna,
Chem Biol Interact. 2000 Jul 3;127(2):163-80. doi: 10.1016/s0009-2797(00)00178-2.
Two isothiocyanates (ITCs) commonly found in human diet, allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC), were tested for genotoxic effects in a battery of assays: Salmonella/microsome assay with TA 98 and TA 100, differential DNA repair assay with E. coli and micronucleus (MN) induction assay with human derived Hep G2 cells. Albeit to a different degree, both ITCs induced genotoxic effects in all test systems. AITC was more genotoxic in bacterial test systems than in Hep G2 cells; in contrast, the effect of PEITC was stronger in Hep G2 cells. In in vivo assays with E. coli indicators in which mice were exposed to relatively high doses of the compounds (90 and 270 mg/kg), AITC induced moderate but significant effects; PEITC failed to induce significant effects in any of the organs. To find out the reason for the weak genotoxicity of AITC and PEITC under in vivo test conditions, we exposed E. coli indicator cells to the test substances in the absence or presence of rat liver homogenate (with and without cofactors), bovine serum albumin (BSA) and human saliva. All of them markedly attenuated the genotoxicity of AITC and PEITC, implying that the test substances are detoxified by direct non-enzymatic binding to proteins. Additional experiments carried out on the mechanistic aspects of AITC and PEITC-induced genotoxicity showed that the compounds induce the formation of thiobarbituric acid reactive substances (TBARS) in Hep G2 cells. Furthermore, in in vitro assays with E. coli, radical scavengers reduced the differential DNA damage induced by AITC and PEITC. The latter two findings give a clue that reactive oxygen species might be involved in the genotoxic effect of the ITCs. Although ITCs have been repeatedly advocated as very promising anticancer agents, the data presented here indicate that the compounds are genotoxic, and probably carcinogenic, in their own right.
在人类饮食中常见的两种异硫氰酸酯（ITC），即烯丙基异硫氰酸酯（AITC）和苯乙基异硫氰酸酯（PEITC），在一系列检测中被测试其遗传毒性作用：使用TA 98和TA 100进行沙门氏菌/微粒体试验、使用大肠杆菌进行差异DNA修复试验以及使用人源Hep G2细胞进行微核（MN）诱导试验。尽管程度不同，但两种ITC在所有测试系统中均诱导了遗传毒性作用。AITC在细菌测试系统中的遗传毒性比在Hep G2细胞中更强；相反，PEITC在Hep G2细胞中的作用更强。在使用大肠杆菌指标的体内试验中，小鼠暴露于相对高剂量的化合物（90和270 mg/kg），AITC诱导了中等但显著的作用；PEITC在任何器官中均未诱导出显著作用。为了找出在体内测试条件下AITC和PEITC遗传毒性较弱的原因，我们将大肠杆菌指示细胞暴露于受试物质中，同时存在或不存在大鼠肝匀浆（有或没有辅因子）、牛血清白蛋白（BSA）和人唾液。所有这些都显著减弱了AITC和PEITC的遗传毒性，这意味着受试物质通过与蛋白质直接非酶结合而被解毒。关于AITC和PEITC诱导遗传毒性的机制方面进行的额外实验表明，这些化合物在Hep G2细胞中诱导硫代巴比妥酸反应性物质（TBARS）的形成。此外，在使用大肠杆菌的体外试验中，自由基清除剂减少了AITC和PEITC诱导的差异DNA损伤。后两个发现提示活性氧可能参与了ITC的遗传毒性作用。尽管ITC一直被反复倡导为非常有前景的抗癌剂，但此处呈现的数据表明这些化合物本身具有遗传毒性，并且可能具有致癌性。
