title: Involvement of N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) in arsenic biomethylation and its role in arsenic-induced toxicity.
abstract: BACKGROUND
  In humans, inorganic arsenic (iAs) is metabolized to methylated arsenical species in a multistep process mainly mediated by arsenic (+3 oxidation state) methyltransferase (AS3MT). Among these metabolites is monomethylarsonous acid (MMAIII), the most toxic arsenic species. A recent study in As3mt-knockout mice suggests that unidentified methyltransferases could be involved in alternative iAs methylation pathways. We found that yeast deletion mutants lacking MTQ2 were highly resistant to iAs exposure. The human ortholog of the yeast MTQ2 is N-6 adenine-specific DNA methyltransferase 1 (N6AMT1), encoding a putative methyltransferase.
  
  
  OBJECTIVE
  We investigated the potential role of N6AMT1 in arsenic-induced toxicity.
  
  
  METHODS
  We measured and compared the cytotoxicity induced by arsenicals and their metabolic profiles using inductively coupled plasma-mass spectrometry in UROtsa human urothelial cells with enhanced N6AMT1 expression and UROtsa vector control cells treated with different concentrations of either iAsIII or MMAIII.
  
  
  RESULTS
  N6AMT1 was able to convert MMAIII to the less toxic dimethylarsonic acid (DMA) when overexpressed in UROtsa cells. The enhanced expression of N6AMT1 in UROtsa cells decreased cytotoxicity of both iAsIII and MMAIII. Moreover, N6AMT1 is expressed in many human tissues at variable levels, although at levels lower than those of AS3MT, supporting a potential participation in arsenic metabolism in vivo.
  
  
  CONCLUSIONS
  Considering that MMAIII is the most toxic arsenical, our data suggest that N6AMT1 has a significant role in determining susceptibility to arsenic toxicity and carcinogenicity because of its specific activity in methylating MMAIII to DMA and other unknown mechanisms.
authors.affiliation: Genes and Environment Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California-Berkeley, Berkeley, California 94720, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Ren
authors.forename: Maria
authors.initials: M
authors.lastname: Aleshin
authors.forename: William J
authors.initials: WJ
authors.lastname: Jo
authors.forename: Russel
authors.initials: R
authors.lastname: Dills
authors.forename: David A
authors.initials: DA
authors.lastname: Kalman
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Vulpe
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
mesh_terms: D002101:Cacodylic Acid / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005656:Fungal Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D013058:Mass Spectrometry; D008745:Methylation; D009942:Organometallic Compounds / Q000378:metabolism / Q000633:toxicity*; D017422:Sequence Analysis, DNA; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism*; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D009942:Organometallic Compounds; C406082:monomethylarsonous acid; D002101:Cacodylic Acid; C000607900:N6AMT1 protein, human; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)