Andrewes Paul, Kitchin Kirk T, Wallace Kathleen
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709, USA.
Chem Res Toxicol. 2003 Aug;16(8):994-1003. doi: 10.1021/tx034063h.
The mechanism of arsenic carcinogenesis is unclear. A complicating factor receiving increasing attention is that arsenic is biomethylated to form various metabolites. Eleven different arsenicals were studied for in vitro genotoxicity to supercoiled DNA (pBR 322 and phiX174). Five arsenicals showed various degrees of positivity-monomethylarsonous acid, dimethylarsinous acid, monomethylarsine, dimethylarsine, and trimethylarsine. Supercoiled DNA, blotted on nitrocellulose filter paper, was exposed to gaseous arsines by suspending the filter paper above aqueous reaction mixtures of sodium borohydride and an appropriate arsenical. All three methylated arsines damaged DNA; inorganic arsine did not. Arsines were generated in situ in reaction mixtures containing DNA by reaction of sodium borohydride with arsenite, monomethylarsonous acid, dimethylarsinous acid, and trimethylarsine oxide, at pH 8.0. Both dimethylarsine and trimethylarsine (generated from 200 micro M dimethylarsinous acid and trimethylarsine oxide, respectively) damaged DNA in less than 30 min. Under certain conditions, the two most potent genotoxic arsines, trimethylarsine and dimethylarsine, are about 100 times more potent than dimethylarsinous acid (the most potent genotoxic arsenical previously known). There was no evidence to suggest that anything other than the arsines caused the DNA damage. Possible models for the biological production of arsines were examined. The coenzymes, NADH and NADPH, are biological hydride donors. When NADH or NADPH (5 mM) were incubated with dimethylarsinous acid (0-2 mM) for 2 h, DNA damage was increased by at least 10-fold. A possible explanation for this result is that these compounds react with dimethylarsinous acid to generate dimethylarsine. DNA was incubated with a dithiol compound, dithioerythritol (5 mM), and trimethylarsine oxide (0.5 mM) for 2 h, and the reduction of trimethylarsine oxide to trimethylarsine resulted in DNA damage.
砷致癌的机制尚不清楚。一个日益受到关注的复杂因素是砷会发生生物甲基化，形成各种代谢产物。研究了11种不同的砷化合物对超螺旋DNA（pBR 322和phiX174）的体外遗传毒性。五种砷化合物呈现出不同程度的阳性反应——一甲基亚胂酸、二甲基亚胂酸、一甲基胂、二甲基胂和三甲基胂。将点样于硝酸纤维素滤纸上的超螺旋DNA悬于硼氢化钠与适当砷化合物的水性反应混合物上方，使其暴露于气态胂中。所有三种甲基化胂均会损伤DNA；无机胂则不会。在pH 8.0的条件下，通过硼氢化钠与亚砷酸盐、一甲基亚胂酸、二甲基亚胂酸和三甲基氧化胂反应，在含有DNA的反应混合物中原位生成胂。二甲基胂和三甲基胂（分别由200 μM二甲基亚胂酸和三甲基氧化胂生成）在不到30分钟内就会损伤DNA。在某些条件下，两种最具遗传毒性的胂——三甲基胂和二甲基胂，其毒性比二甲基亚胂酸（此前已知的最具遗传毒性的砷化合物）强约100倍。没有证据表明除胂之外的其他任何物质会导致DNA损伤。研究了胂生物生成的可能模型。辅酶NADH和NADPH是生物氢供体。当NADH或NADPH（5 mM）与二甲基亚胂酸（0 - 2 mM）孵育2小时时，DNA损伤至少增加了10倍。对此结果的一种可能解释是，这些化合物与二甲基亚胂酸反应生成了二甲基胂。将DNA与二硫醇化合物二硫赤藓糖醇（5 mM）和三甲基氧化胂（0.5 mM）孵育2小时，三甲基氧化胂还原为三甲基胂导致了DNA损伤。
