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PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN
Citation:
Ahmad, S AND K T. Kitchin. PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN. Presented at Int'l Symposium on Carcinogenic Metals, Australia, July 1-5, 2001.
Description:
Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin.
Arsenic causes cancer in human skin, urinary bladder, lung, liver and kidney and is a significant world-wide public health problem. Although the metabolism of inorganic arsenic is fairly well understood, the precise mechanism of arsenic induced carcinogenicity in humans is not known. In our recent studies we noted that both dimethylarsinic acid (DMA(V)) and dimethylarsinous acid (DMA(III)) release iron from human liver ferritin (HLF) either with or without the presence of ascorbic acid (AA) (an endogenous reducing agent). Recent studies of others indicate that arsenic may generate reactive oxygen species (ROS) (e. g. dimethylarsenic peroxyl radical, superoxide anion or hydroxyl radicals ), possibly via iron-dependent mechanisms, causing cellular toxicity and/or carcinogenicity. In the studies presented here, we investigated the interaction between arsenic species, HLF and a DNA target. A pBR322 plasmid DNA damage assay was used to study the pro-oxidant activity of free iron released from HLF. Little to no DNA damage was caused by single exposure to As(V), As(III), MMA(V), MMA(III) or DMA(V). However, DMA(III) alone or with HLF nicked plasmid DNA to a low or medium extent, respectively. Further, the combination of DMA(III), HLF and M increased the nicking in plasmid DNA to high amounts as compared to either (a) DMA(/II) and HLF or (b) HI-F and AA. This may be due to an increase in iron released from HLF by DMA(III) in the presence of M. No ROS scavengers such as superoxide dismutase, mannitol, potassium iodide or sodium azide could completely inhibit this plasmid DNA damage. However, the presence of catalase further increased the degree of DNA damage. Based on these and other in vitro results, we suggest that the combination of the methylated trivalent arsenic species DMA(IIl) (an exogenous factor) and M (an endogenous factor) release iron from HLF, increase iron-
dependent ROS formation and damage DNA in vivo. The DNA damage caused by iron-
dependent ROS could be a mechanism of action of arsenic carcinogenesis in human.
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