甲基化砷化合物、抗坏血酸和人肝脏铁蛋白导致的质粒DNA损伤

Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin.

作者信息

Ahmad Sarfaraz, Kitchin Kirk T, Cullen William R

机构信息

Mercer University School of Medicine, Division of Basic Medical Sciences, 1550 College Street,, Macon, GA 31207, USA.

出版信息

Toxicol Lett. 2002 Jul 7;133(1):47-57. doi: 10.1016/s0378-4274(02)00079-6.

DOI:10.1016/s0378-4274(02)00079-6

PMID:12076509

Abstract

Both dimethylarsinic acid (DMA(V)) and dimethylarsinous acid (DMA(III)) release iron from human liver ferritin (HLF) with or without the presence of ascorbic acid. With ascorbic acid the rate of iron release from HLF by DMA(V) was intermediate (3.37 nM/min, P<0.05) and by DMA(III) was much higher (16.3 nM/min, P<0.001). No pBR322 plasmid DNA damage was observed from in vitro exposure to arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)) or DMA(V) alone. DNA damage was observed following DMA(III) exposure; coexposure to DMA(III) and HLF caused more DNA damage; considerably higher amounts of DNA damage was caused by coexposure of DMA(III), HLF and ascorbic acid. Diethylenetriaminepentaacetic acid (an iron chelator), significantly inhibited DNA damage. Addition of catalase (which can increase Fe(2+) concentrations) further increased the plasmid DNA damage. Iron-dependent DNA damage could be a mechanism of action of human arsenic carcinogenesis.

摘要

二甲基胂酸（DMA(V)）和二甲基亚胂酸（DMA(III)）在有或没有抗坏血酸存在的情况下，都能从人肝铁蛋白（HLF）中释放铁。在有抗坏血酸的情况下，DMA(V)从HLF中释放铁的速率处于中等水平（3.37 nM/分钟，P<0.05），而DMA(III)的速率则高得多（16.3 nM/分钟，P<0.001）。体外单独暴露于砷酸盐（iAs(V)）、亚砷酸盐（iAs(III)）、一甲基胂酸（MMA(V)）、一甲基亚胂酸（MMA(III)）或DMA(V)时，未观察到pBR322质粒DNA损伤。暴露于DMA(III)后观察到DNA损伤；DMA(III)与HLF共同暴露导致更多DNA损伤；DMA(III)、HLF和抗坏血酸共同暴露造成的DNA损伤量明显更高。二乙烯三胺五乙酸（一种铁螯合剂）显著抑制了DNA损伤。添加过氧化氢酶（可增加Fe(2+)浓度）进一步增加了质粒DNA损伤。铁依赖性DNA损伤可能是人砷致癌作用的一种作用机制。