Relative genotoxic potency of arsenic and its methylated metabolites
Relative genotoxic potency of arsenic and its methylated metabolites
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DOI：
10.1016/s1383-5742(97)00003-3
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发表时间：
1997-06-01
影响因子：
5.3
通讯作者：
Doerr, CL
中科院分区：
文献类型：
--
作者：
Moore, MM;HarringtonBrock, K;Doerr, CL
砷是少数已确定的人类致癌物之一，但在使用标准生物测定方案时，尚未显示会在啮齿动物中致癌。这种明显的物种间差异的原因尚不清楚，但可能与人类和啮齿动物在解毒能力方面的差异有关。砷的解毒可能通过甲基化途径发生。事实上，如果甲基化确实能解毒砷，人们可以预测，甲基化砷可能比无机砷的遗传毒性更小。为了验证无机砷比有机砷更具有致突变性的假设，我们测试了亚砷酸钠、砷酸钠、一甲基胂酸（MMA）和二甲基胂酸（DMA）的相对致突变性和致裂性。我们使用了L5178Y/TK+/-小鼠淋巴瘤试验，该试验允许检测化学物质诱导的广谱不同类型的遗传损伤。亚砷酸钠和砷酸钠分别在浓度为1 ~ 2 μ g/ml和10 ~ 14 μ g/ml时具有活性。MMA在2500 ~ 5000 μ g/ml之间有活性；而DMA几乎需要10000 μ g/ml才能诱导基因毒性反应。因此，有机砷作为诱变剂的效力比无机砷小得多。这四种砷似乎都是通过引起染色体突变的机制起作用的。
Arsenic is one of the few identified human carcinogens that has yet to be shown to cause cancer in rodents when the standard bioassay protocols are used. The reasons for this apparent interspecies difference are unclear but may be related to differences between humans and rodents in their detoxification capabilities. Detoxification of arsenic may occur through a methylation pathway. If, in fact, methylation does detoxify arsenic, one would predict that the methylated arsenicals might be less genotoxic than the inorganic arsenicals. To evaluate the hypothesis that the inorganic arsenicals are more mutagenic than the organic arsenicals, we tested sodium arsenite, sodium arsenate, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) for their relative mutagenic and clastogenic potentials. We used the L5178Y/TK+/- mouse lymphoma assay which allows the detection of chemicals inducing a broad spectrum of different types of genetic damage. Sodium arsenite and sodium arsenate were active at concentrations of 1-2 mu g/ml and 10-14 mu g/ml, respectively. MMA was active between 2500-5000 mu g/ml; while DMA required almost 10 000 mu g/ml to induce a genotoxic response. The organic arsenicals are thus much less potent as mutagenic agents than the inorganic arsenicals. All four of these arsenicals appear to act by mechanisms that cause chromosomal mutations.