Role of metallothionein as an inhibitory factor in metal carcinogenesis

为了阐明金属硫蛋白(MT)在金属致癌中的作用，我们研究了MT对无机砷的代谢产物二甲基砷酸(DMA)的遗传毒性和致癌性的影响，并利用MT基因缺失的小鼠抑制了MT的主要亚型MT-1和MT-II的表达。MT对二甲基亚硝胺和镉中毒的影响：在MT缺失型小鼠和野生型小鼠中，DMA引起外周血细胞DNA链断裂，并使血清和尿中8-0HdG水平升高，且呈剂量依赖关系。但MT缺失型小鼠的DNA链断裂和8-0HdG的增加明显高于野生型小鼠。另一方面，在镉引起的尿8-0HdG升高中，MT缺失型小鼠比野生型小鼠更易受影响。这些结果提示MT对DNA和Cd的遗传毒性具有保护作用。MT对DMA和Cd致癌作用的影响：我们用MT缺失型小鼠和野生型小鼠检测了DMA和Cd诱发肿瘤的作用，而在这两种类型的小鼠中DMA和Cd均不诱发肿瘤。因此，在本研究中，DMA和Cd的剂量是不够的。在未来的研究中，有必要在MT基因缺失的小鼠和野生型小鼠上，利用不同的剂量和给药时间来检测MT对DMA和Cd致癌作用的影响。

To elucidate the role of metallothionein (MT) in the metal carcinogenesis, we examined the effect of MT on the genotoxicity and carcinogenicity caused by dimethylarsenic acid (DMA) that is a metabolite of inorganic arsenic, and cadnrium using MT-null mice whose expression of MT-1 and MT-II, major isoforms of MT, were suppressed.1. Effect of MT on the enotoxicit of DMA and cadmium :DMA produced DNA strand breaks in peripheral blood cells and increased 8-0HdG Ievels in serum and urine in both MT-null mice and wild-type mice in a dose-dependent manner. However, the production of DNA strand breaks and the increase of 8-0HdG were significantly higher in the MT null mice than that of the wild-type mice. On the other hand, in the increase of urinary 8-0HdG by cadmium, MT-null mice were more susceptible than wild-type mice. These results suggest that MT plays a protective role against the genotoxicity of DMA and cadmium.2. Effect of MT on the carcino enicit of DMA and cadmium :We examined the induction of tumors by DMA and cadmium using MT-null mice and wild-type mice, whereas the tumor was not induced by DMA and cadmium in both types of mice. Thus, doses of DMA and cadmium were not adequate in this study. In the future study, it is necessary to examine the effect of MT on the carcinogenicity of DMA and cadmium using various conditions of dose and administration period in MT-null mice and wild-type mice.