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Catalase Has a Key Role in Protecting Cells from the Genotoxic Effects of Monomethylarsonous Acid, a Highly Active Metabolite of Arsenic
Citation:
Muniz Ortiz, J., K. Wallace, F. Leinishch, M. Kadiiska, R. Mason, AND A. Kligerman. Catalase Has a Key Role in Protecting Cells from the Genotoxic Effects of Monomethylarsonous Acid, a Highly Active Metabolite of Arsenic. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 54(5):317-26, (2013).
Impact/Purpose:
This is a scientific research paper describing how the gene for catalase affects sensitivity to an arrsenical. It implicates reactive oxygen species as a causitive agent in the genetic damage induced by arsenic.
Description:
ABSTRACT Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic’s exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. The author's studies are centered on identifying a reactive species involved in the genotoxicity of arsenic using a catalase (CAT) knock-out mouse model that is impaired in its ability to break down hydrogen peroxide (H2O2). The authors assessed the induction of DNA damage using the comet assay following exposure of mouse Cat+/+ and Cat-/- primary splenic lymphocytes to monomethylarsonous acid (MMAIII) to identify the potential role of H2O2 in mediating cellular effects of this metalloid. Our results showed that the Cat-/- lymphocytes are more susceptible to MMAIII than the Cat+/+ lymphocytes by a small (1.5-fold), but statistically significant difference. Catalase activity assays demonstrated that liver tissue has ~3 times more CAT activity than lymphocytes. Therefore, comet assays were performed on primary Cat+/+, Cat+/-, and Cat-/- hepatocytes to determine if the Cat-/- cells were more susceptible to MMAIII than lymphocytes. Results showed that the Cat-/- hepatocytes exhibit higher levels of DNA strand breakage than the Cat+/+ (~5-fold) and Cat+/- (~2-fold) hepatocytes exposed to MMAIII. Electron spin resonance using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin trap agent detected the generation of •OH via MMAIII when H2O2 was present. Our experiments suggest that catalase is involved in protecting cells against the genotoxic effects of the •OH generated by MMAIII. Key words: arsenicals, mode of action, reactive oxygen species, DNA damage, Comet Assay