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M201151200v1
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Papers In Press, published online ahead of print March 7, 2002
J. Biol. Chem, 10.1074/jbc.M201151200
Submitted on February 4, 2002
Revised on March 5, 2002
Accepted on March 7, 2002

Vitamin C prevents DNA mutation induced by oxidative stress

Eugene A. Lutsenko, Juan M. Carcamo, and David W. Golde

Mol. Hematology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Corresponding Author: d-golde{at}ski.mskcc.org

The precise role of vitamin C in the prevention of DNA mutations is controversial. While ascorbic acid has strong antioxidant properties, it also has pro-oxidant effects in the presence of free transition metals. Vitamin C was recently reported to induce the decomposition of lipid hydroperoxides independent of metal interactions, suggesting that it could cause DNA damage. In order to directly address the role of vitamin C in maintaining genomic integrity, we developed a genetic system for quantifying guanine base mutations induced in human cells under oxidative stress. The assay utilized a plasmid construct encoding the cDNA for chloramphenicol acetyl transferase modified to contain an amber stop codon, which was restored to wild type by G to T transversion induced by oxidative stress. The mutation frequency was determined from the number of plasmids containing the wild type chloramphenicol acetyl transferase gene rescued from oxidatively stressed cells. Cells were loaded with vitamin C by exposing them to dehydroascorbic acid (DHA), thereby avoiding transition metal related pro-oxidant effects of ascorbic acid. We found that vitamin C loading resulted in substantially decreased mutations induced by H2O2. Depletion of glutathione led to cytotoxicity and an increase in H2O2-induced mutation frequency, however mutation frequency was prominently decreased in depleted cells preloaded with vitamin C. The mutation results correlated with a decrease in total 8-oxo-guanine (8-oxo-dG) measured in genomic DNA of cells loaded with vitamin C and oxidatively stressed. These findings directly support the concept that high intracellular concentrations of vitamin C can prevent oxidation-induced mutations in human cells.


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