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PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN
Citation:
Ahmad, S, K T. Kitchin, AND W. R. Cullen. PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN. TOXICOLOGY LETTERS 133(1):47-57, (2001).
Description:
PLASMID DNA DAMAGE CAOUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN
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. In the presence of ascorbic acid the rate of iron release from HLF by DMA(V) was intermediate (3.37 ,uM/min, p < 0.05) and by DMA(III) was much higher (16.3 ,uM/min, p < 0.001 ). The pro-oxidant activity of free iron released from HLF was studied by using a pBR322 plasmid DNA damage assay system in vitro. No plasmid DNA damage was observed from exposure to arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)) and DMA(V) alone. DMA(III) exposure alone caused some nicking in plasmid DNA. However, the DNA damage was considerably increased by coexposure to DMA(III) and HLF. The cleavage of plasmid DNA was further increased by exposure of HLF, DMA(III) and ascorbic acid together. This may be due to increases in iron released from HLF by DMA(III) and ascorbic acid.
The presence of diethylenetriaminepentaacetic acid (an iron chelator), significantly inhibited the cleavage of plasmid DNA. Addition of catalase (which can increase Fe++ concentrations) further increased the plasmid DNA 3 damage. This iron-dependent DNA damage could be a mechanism of action of arsenic carcinogenesis in humans.
Key words: Arsenic; Iron; Human liver ferritin; DNA damage; Rea~tive oxygen species; dimethylarsinous acid, DMA(III).