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arsenite in various human cell lines47. Furthermore, antioxidant enzymes such as SODreduce the incidence of sister chromatid exchangesinduced by arsenite in cultured human lymphocytes 48.As SOD and catalase are relatively large moleculeswith molecular weights of 30 and 250 kDa, respectively,they are highly unlikely to pass across the cell membranewithout being phagocytozed. The ability of SOD andcatalase to suppress the mutagenicity of arsenic inmammalian cells is consistent with the ESR findingsdescribed above: that arsenic induces hydrogen peroxideas a precursor of hydroxyl radicals in AL cells 27.Because hydrogen peroxide is freely diffusible betweenintracellular and extracellular space, addition of extracellularantioxidants is likely to reduce the intracellularoxidative stress induced by arsenite treatment and, subsequently,result in reduced genotoxic damage. The exactpathway, however, remains to be elucidated.Induction of oxidative DNA damage by arsenic inmammalian cells.

 

If generation of ROS is one of the major pathwaysfor arsenic-mediated genotoxicity, then it should beexpected to induce specific DNA lesions consistent withoxidative damage. One of the most common oxidativeDNA lesions is 8-hydroxy-2V-deoxyguanosine (8-OHdG). Use of a monoclonal antibody specific for 8-OHdG with immunoperoxidase staining has providedevidence that arsenic treatment (4 Ag/ml for 24 h)increases the level of 8-OHdG in AL cells by more than2-fold compared with that in nontreated controls 45.Furthermore, addition of SOD and catalase reduces thisincrease by 75%. These findings provide additionalproof that ROS mediate the genotoxic response inmammalian cells on treatment with sodium arsenite.Furthermore, there is evidence that 8-OHdG has alsobeen detected in the skin of patients with arsenic-relatedBowen’s disease 49 and in the liver of rats exposed toDMAV 50.

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ROLE OF ROS IN MEDIATING THE GENOTOXICITY OFMETHYLATED ARSENIC

 

As mentioned earlier in this article, inorganic arsenicexists in nature in two major forms: the trivalent As3+and the pentavalent As5+ 8. Trivalent arsenic issignificantly more toxic and carcinogenic than thepentavalent form. In mammals, ingested inorganic arsenicis readily metabolized by methylation into thepentavalent methylated species, namely, the monomethylarsonicacid (MMAV) and dimethylarsinic acid(DMAV) 51,52. The methylation process has beenconsidered for many years to be a critical detoxifyingprocess 8,53. These methylated species are much lesstoxic and genotoxic than the inorganic arsenic species54,55 and are readily detectable in the urine ofexposed human population. However, with improvedanalytical assays, there is recent evidence that thetrivalent methylated species, monomethylarsonous acid(MMAIII) and dimethylarsinous acid (DMAIII), are oftendetected in human urine samples as well 56. Furthermore,these trivalent methylated arsenic species are farmore cytotoxic and DNA damaging than the inorganicmetalloid 55,57. Using the BX174 DNA nicking assaytogether with known inhibitors of ROS activities, thereis evidence that both MMAIII and DMAIII exert theirDNA-damaging effects through an intermediate involvingROS production 57. Furthermore, studies usingESR and the spin trap 5,5-dimethyl-1-pyrroline-N-oxide(DMPO) suggest that these radical species to be hydroxylradicals 57.

Arsenic upregulates MMP-9 and and inhibits wound repair

In high-throughput protein screening experiments with lowdosearsenic exposure, we found reduced expression of proteinsassociated with cellular migration in mouse lung tissue(26) and alteration of a specific wound repair protein marker inmouse bronchoalveolar fluid (27). Additional microarray experimentson lung tissue from mice fed low-dose arsenicrevealed several changes in extracellular matrix (ECM) proteinexpression and a large increase in matrix 

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