Vahter M
Sci Prog. 1999;82 ( Pt 1)(1):69-88. doi: 10.1177/003685049908200104.
Thousands of people in different parts of the world are exposed to arsenic via drinking water or contaminated soil or food. The high general toxic of arsenic has been known for centuries, and research during the last decades has shown that arsenic is a potent human carcinogen. However, most experimental cancer studies have failed to demonstrate carcinogenicity in experimental animals, indicating marked variation in sensitivity towards arsenic toxicity between species. It has also been suggested that there is a variation in susceptibility among human individuals. One reason for such variability in toxic response may be variation in metabolism. Inorganic arsenic is methylated in humans as well as animals and micro-organisms, but there are considerable differences between species and individuals. In many, but not all, mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are more rapidly excreted in urine than is the inorganic arsenic, especially the trivalent form (AsIII, arsenite) which is highly reactive with tissue components. Absorbed arsenate (AsV) is reduced to trivalent arsenic (AsIII) before the methyl groups are attached. It has been estimated that as much as 50-70% of absorbed AsV is rapidly reduced to AsIII, a reaction which seems to be common for most species. In most experimental animal species, DMA is the main metabolite excreted in urine. Compared to human subjects, very little MMA is produced. However, the rate of methylation varies considerably between species, and several species, e.g. the marmoset monkey and the chimpanzee have been shown not to methylate inorganic arsenic at all. In addition, the marmoset monkey accumulates arsenic in the liver. The rat, on the other hand, has an efficient methylation of arsenic but the formed DMA is to a large extent accumulated in the red blood cells. As a result, the rat shows a low rate of excretion of arsenic. In both human subjects and rodents exposed to DMA, about 5% of the dose is excreted in the urine as trimethylarsine oxide. It is obvious from studies on human volunteers exposed to specified doses of inorganic arsenic that the rate of excretion increases with the methylation efficiency, and there are large inter-individual variations in the methylation of arsenic. Recent studies on people exposed to arsenic via drinking water in northern Argentina have shown unusually low urinary excretion of MMA. Furthermore, children had a lower degree of methylation of arsenic than adults. Some studies indicate a lower degree of arsenic methylation in men than in women, especially during pregnancy. Whether the observed differences in methylation of arsenic are associated with variations in the susceptibility of arsenic remains to be investigated.
世界不同地区的数千人通过饮用水、受污染的土壤或食物接触到砷。砷具有高毒性，几个世纪以来人们都已熟知，过去几十年的研究表明，砷是一种强效的人类致癌物。然而，大多数实验性癌症研究未能在实验动物中证明其致癌性，这表明不同物种对砷毒性的敏感性存在显著差异。也有人提出，人类个体之间的易感性也存在差异。毒性反应存在这种变异性的一个原因可能是代谢的差异。无机砷在人类、动物和微生物体内都会发生甲基化，但物种和个体之间存在相当大的差异。在许多（但不是所有）哺乳动物物种中，无机砷会甲基化为甲基胂酸（MMA）和二甲基胂酸（DMA），它们在尿液中的排泄速度比无机砷更快，尤其是三价形式（AsIII，亚砷酸盐），它与组织成分反应性很强。在连接甲基之前，吸收的砷酸盐（AsV）会还原为三价砷（AsIII）。据估计，高达50 - 70%的吸收的AsV会迅速还原为AsIII，这一反应似乎在大多数物种中都很常见。在大多数实验动物物种中，DMA是尿液中排泄的主要代谢产物。与人类受试者相比，产生的MMA很少。然而，甲基化速率在不同物种之间差异很大，并且已经表明一些物种，例如狨猴和黑猩猩根本不会使无机砷甲基化。此外，狨猴会在肝脏中积累砷。另一方面，大鼠对砷有高效的甲基化作用，但形成的DMA在很大程度上会积累在红细胞中。结果，大鼠的砷排泄率很低。在接触DMA的人类受试者和啮齿动物中，大约5%的剂量会以氧化三甲基胂的形式从尿液中排泄。从对接触特定剂量无机砷的人类志愿者的研究中可以明显看出，排泄率会随着甲基化效率的提高而增加，并且砷的甲基化在个体之间存在很大差异。最近对阿根廷北部通过饮用水接触砷的人群的研究表明，MMA的尿排泄量异常低。此外，儿童的砷甲基化程度低于成年人。一些研究表明，男性砷甲基化程度低于女性，尤其是在怀孕期间。观察到的砷甲基化差异是否与砷易感性的差异有关，仍有待研究。
