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DIVALENT METAL TRANSPORTER-1 REGULATION BY IRON AND VANADIUM MODULATES HYDROGEN PEROXIDE-INDUCED DNA DAMAGE IN LUNG CELLS
Citation:
MOLINELLI, A. R., A. J. GHIO, AND M. C. MADDEN. DIVALENT METAL TRANSPORTER-1 REGULATION BY IRON AND VANADIUM MODULATES HYDROGEN PEROXIDE-INDUCED DNA DAMAGE IN LUNG CELLS. Presented at Society of Toxicology Annual Meeting, San Diego, CA, March 05 - 09, 2006.
Description:
The divalent metal transporter-1 (DMT1) participates in the detoxification of metals that can damage lung epithelium. Elevated iron levels increase the expression of DMT1 in bronchial epithelial cells stimulating its uptake and storage in ferritin, thus making iron unavailable to participate in the generation of extracellular reactive oxygen species (ROS). However, it has also been suggested that this uptake might increase intracellular ROS formation. To further test whether increased DMT1 expression is protective, we exposed human bronchial epithelial cells (BEAS-2B) to 100 ?M ferric ammonium citrate (FAC) or 50 ?M vanadium sulfate (which downregulates DMT1 expression) for 4 h. Cells were then washed and incubated for 20 h in media. After this period the cells were washed and exposed to 100 ?M FAC with or without 20 ?M H2O2 (an endogenously produced oxidant) for 30 min. After the exposure the comet assay was used to assess DNA single strand breaks (SSBs). Cells pre-treated with VOSO4 and subsequently exposed to FAC + H2O2 had a statistically significant (p < 0.05) increase in DNA SSBs (i.e., comet area = 1252 ?m2) when compared to control cells pre-treated with cell media alone (546 ?m2). Cells that were pre-treated with FAC had a non-significant decrease in DNA SSBs (419 ?m2) compared to the control cells. Among cell groups that were incubated with FAC without H2O2, there were no increased SSBs (i.e., DNA areas of 356 ? 384 ?m2). These results provide further evidence that increased DMT1 expression serves as a protective mechanism in the lungs by stimulating cells to intracellularly transport and bind iron, thus making it unavailable to participate in ROS generation and increased DNA SSBs. [This abstract may not reflect official EPA policy. AM supported by EPA/UNC T829472].