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，我们利用MT-1和MT- ii （MT的主要亚型）表达被抑制的MT-1缺失小鼠，研究了MT对无机砷和镉的代谢物二甲基砷酸（DMA）引起的遗传毒性和致癌性的影响。MT对DMA和镉毒性的影响：在MT-null小鼠和野生型小鼠中，DMA在外周血细胞中产生DNA链断裂，并以剂量依赖的方式增加血清和尿液中8-0HdG水平。然而，MT缺失小鼠DNA链断裂的产生和8-0HdG的增加明显高于野生型小鼠。另一方面，在镉增加尿8-0HdG方面，MT-null小鼠比野生型小鼠更敏感。这些结果表明，MT对DMA和镉的遗传毒性具有保护作用。MT对DMA和镉致癌性的影响：我们用MT-null小鼠和野生型小鼠检测了DMA和镉对肿瘤的诱导作用，而两种类型小鼠的肿瘤均未被DMA和镉诱导。因此，在本研究中，DMA和镉的剂量是不够的。在未来的研究中，有必要在MT-null小鼠和野生型小鼠中，通过不同剂量和给药时间条件，研究MT对DMA和镉致癌性的影响。

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.