Partridge Michael A, Huang Sarah X L, Hernandez-Rosa Evelyn, Davidson Mercy M, Hei Tom K
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Cancer Res. 2007 Jun 1;67(11):5239-47. doi: 10.1158/0008-5472.CAN-07-0074.
Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A(L) cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells.
砷是一种已被充分证实的人类致癌物，全球数百万人长期通过饮用水摄入砷。最近的证据表明砷是一种基因毒性致癌物。此外，我们已经证明线粒体介导了砷在哺乳动物细胞中的诱变作用，因为砷在缺乏线粒体DNA（mtDNA）的细胞中不会诱导核突变。利用人-仓鼠杂交A(L)细胞，我们在此表明砷通过降低细胞色素c氧化酶功能和氧气消耗但增加柠檬酸合酶功能来改变线粒体功能。这些改变与mtDNA拷贝数的减少和大的异质性mtDNA缺失的增加相关。此外，从连续用砷处理的培养物中定期分离的mtDNA并没有始终显示相同的缺失模式，这表明线粒体基因组受到了反复和持续的损伤。这些数据支持了线粒体，特别是mtDNA，是砷在哺乳动物细胞中诱变作用的重要靶点这一理论。
