title: Interactive Effects of N6AMT1 and As3MT in Arsenic Biomethylation.
abstract: In humans, arsenic is primarily metabolized by arsenic (+3 oxidation state) methyltransferase (As3MT) to yield both trivalent and pentavalent methylated metabolites. We recently reported that the putative N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) can biotransform monomethylarsonous acid (MMA(III)) to dimethylarsinic acid, conferring resistance of human cells to arsenic exposure. To further decipher the role of N6AMT1 and its interaction with As3MT in arsenic biomethylation, we examined the relative contribution of N6AMT1 and As3MT in metabolizing arsenic using several newly modified UROtsa human urothelial cells, ie, UROtsa cells with either a constant level of N6AMT1 or As3MT in combination with an inducible level of As3MT or N6AMT1, respectively. Our analysis confirmed the involvement of N6AMT1 in MMA(III) biomethylation but not for inorganic arsenic. In a comparable level of N6AMT1 and As3MT, the effect of N6AMT1 mediated MMA(III) biomethylation was obscured by the action of As3MT. Furthermore, we showed that the levels of N6AMT1 and As3MT proteins varied among and within human normal and cancerous tissues. Overall, the data showed that N6AMT1 has a role in MMA(III) biomethylation, but its effect is relatively minor and limited compared with As3MT. In addition, the varied levels and distributions of N6AMT1 and As3MT among human tissues may potentially contribute to the tissue specificity and susceptibility to arsenic toxicity and carcinogenicity.
authors.affiliation: *Department of Epidemiology and Environmental Health;
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: *Department of Epidemiology and Environmental Health;
authors.forename: Yichen
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Chemistry; and.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: *Department of Epidemiology and Environmental Health;
authors.forename: Xushen
authors.initials: X
authors.lastname: Chen
authors.affiliation: *Department of Epidemiology and Environmental Health;
authors.forename: Abreu
authors.initials: A
authors.lastname: Carina
authors.affiliation: *Department of Epidemiology and Environmental Health;
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Chemistry; and.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Aga
authors.affiliation: *Department of Epidemiology and Environmental Health; Department of Pharmacology and Toxicology, The State University of New York, Buffalo, New York xuefengr@buffalo.edu.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Ren
mesh_terms: D001151:Arsenic / Q000493:pharmacokinetics*; D002461:Cell Line, Transformed; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D013058:Mass Spectrometry; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism*
chemical_list: D008780:Methyltransferases; C505756:AS3MT protein, human; C000607900:N6AMT1 protein, human; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); D001151:Arsenic
keywords: As3MT; N6AMT1; arsenic metabolism