Requirement of Arsenic Biomethylation for Oxidative DNA Damage

Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 11/2009; 101(24):1670-81. DOI: 10.1093/jnci/djp414
Source: PubMed


Inorganic arsenic is an environmental carcinogen that may act through multiple mechanisms including formation of methylated derivatives in vivo. Sodium arsenite (up to 5.0 microM) renders arsenic methylation-competent TRL1215 rat liver epithelial cells tumorigenic in nude mice at 18 weeks of exposure and arsenic methylation-deficient RWPE-1 human prostate epithelial cells tumorigenic at 30 weeks of exposure. We assessed the role of arsenic biomethylation in oxidative DNA damage (ODD) using a recently developed immuno-spin trapping method.
Immuno-spin trapping was used to measure ODD after chronic exposure of cultured TRL1215 vs RWPE-1 cells, or of methylation-competent UROtsa/F35 vs methylation-deficient UROtsa human urothelial cells, to sodium arsenite. Secreted matrix metalloproteinase (MMP)-2 and -9 activity, as analyzed by zymography, cellular invasiveness by using a transwell assay, and colony formation by using soft agar assay were compared in cells exposed to arsenite with and without selenite, an arsenic biomethylation inhibitor, to assess the role of ODD in the transition to an in vitro cancer phenotype.
Exposure of methylation-competent TRL1215 cells to up to 1.0 microM sodium arsenite was followed by a substantial increase in ODD at 5-18 weeks (eg, at 16 weeks with 1.0 microM arsenite, 1138% of control, 95% confidence interval [CI] = 797% to 1481%), whereas exposure of methylation-deficient RWPE-1 cells to up to 5.0 microM arsenite did not increase ODD for a 30-week period. Inhibition of arsenic biomethylation with sodium selenite abolished arsenic-induced ODD and invasiveness, colony formation, and MMP-2 and -9 hypersecretion in TRL1215 cells. Arsenic induced ODD in methylation-competent UROtsa/F35 cells (eg, at 16 weeks, with 1.0 microM arsenite 225% of control, 95% CI = 188% to 262%) but not in arsenic methylation-deficient UROtsa cells, and ODD levels corresponded to the levels of increased invasiveness, colony formation, and hypersecretion of active MMP-2 and -9 seen after transformation to an in vitro cancer phenotype.
Arsenic biomethylation appears to be obligatory for arsenic-induced ODD and appears linked in some cells with the accelerated transition to an in vitro cancer phenotype.

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    • "Other reports have previously indicated that ODD is meaningful for arsenic-induced cancer and disease, although based on indirect evidences. Among them, the work of Kojima et al. (2009) showed that chronic arsenite exposure of methylation-competent cells was followed by a rise in ODD with a subsequent acquisition of the in vitro characteristics of transformed cells. Results lead authors to conclude that biomethylation of arsenic compounds appear to be mandatory for ODD generation and linked to an increase in their carcinogenicity (Sampayo-Reyes et al. 2010). "
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    • "After entering the cells, arsenic undergoes methylation reaction by the arsenite methyltransferase (AS3MT) enzyme producing several methylated arsenic compounds (Kojima et al., 2009). Arsenic methylation was initially believed to be a detoxification reaction (Gebel, 2002), but more recent evidence invalidated such a hypothesis showing an increased toxicity of specific methylated intermediate metabolites (Kojima et al., 2009; Sun et al., 2014). "
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    • "Numerous studies have indicated that arsenic induces DNA damage (Kessel et al., 2002; Bhadauria and Flora, 2007; Lee and Ho, 1995; Dong and Luo, 1993; Kojima et al., 2009) and chromosome aberration such as chromosomal aneuploidy (Ochi et al., 1984; Sciandrello et al., 2002, 2004). MMA and DMA are directly genotoxic (Mass et al., 2001). "
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