Superoxide dismutase protects cells from DNA damage induced by trivalent methylated arsenicals

Abstract

Superoxide dismutase (SOD) catalyzes the conversion of superoxide to hydrogen peroxide. Heterozygous mice of strain B6;129S7-Sod1(tm1Leb)/J were obtained from Jackson Laboratories and bred to produce offspring that were heterozygous (+/Sod1(tm1Leb)), homozygous wild-type (+/+), and homozygous knockout (Sod1(tm1Leb) /Sod1(tm1Leb)) for the Cu/Zn superoxide dismutase (Sod1) gene. Splenocytes from these mice were exposed to several concentrations of either sodium arsenite (As3 [0-200 μM]), monomethylarsonous acid (MMA3 [0-10 μM]), or dimethylarsinous acid (DMA3 [0-10 μM]) for 2 hr. Cells were then examined for DNA damage using the alkaline single cell gel electrophoresis assay. Methyl methanesulfonate (MMS) was used as a positive control. Splenocytes from each of the three genotypes for Sod1 were equally sensitive to MMS and As3. However, at equimolar concentrations, DMA3 and MMA3 produced significantly more DNA damage in the homozygous knockout mouse splenocytes than in the splenocytes from the wild-type or heterozygous mice. These findings suggest that superoxide is involved either directly or indirectly in producing DNA damage in cells exposed to trivalent methylated arsenicals. These arsenicals may generate reactive oxygen species that damage DNA. This DNA damage may be a key factor in initiating cancer in vivo.