title: Urinary sulfur-containing metabolite produced by intestinal bacteria following oral administration of dimethylarsinic acid to rats.
abstract: Our long-term oral administration of dimethylarsinic acid (DMAV) in rats revealed that three unidentified metabolites, M-1, M-2, and M-3, were detected in urine and feces. DMAV and trimethylarsine oxide (TMAO) were converted to M-2 and M-3 and M-1 by Escherichia coli strain A3-6 isolated from the ceca of DMAV-administered rats, respectively. In this study, we report on the mechanism of production and the chemical properties of these unknown metabolites. To investigate the pattern of conversion of DMAV or TMAO by A3-6 in the presence of cysteine (Cys), arsenic metabolites of DMAV or TMAO in medium after incubation with A3-6 and Cys were analyzed by liquid chromatography with inductively coupled plasma mass spectrometry (LC-ICP-MS). DMAV was reduced to dimethylarsinous acid (DMAIII) to form M-2 in the presence of Cys and A3-6, and M-2 was further converted to M-3. TMAO was rapidly converted to M-1 by A3-6. The cytotoxicity of the unidentified metabolites was investigated. M-2 was more cytotoxic than DMAV, M-1, and M-3 in V79 cells. The cytotoxicity of M-2 in HL-60 cells was decreased by the addition of superoxide dismutase, suggesting that the cytotoxicity of M-2 might be due to the production of reactive oxygen species. In addition, we examined the chemical properties of M-2 by LC-ICP-MS and LC-MS. M-2 was oxidized to DMAV by hydrogen peroxide, suggesting that M-2 may be a reduced form of DMAV. M-2 was consistent with the reactant of DMAV with metabisulfite-thiosulfate reagent but not DMAIII by analyses of LC-ICP-MS and LC-MS. The molecular weight of M-2 was 154, and M-2 was a sulfur-containing metabolite.
authors.affiliation: Department of Preventive Medicine and Environmental Health, Osaka City University Medical School, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. kyoshida@med.osaka-cu.ac.jp
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshida
authors.forename: Koichi
authors.initials: K
authors.lastname: Kuroda
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Date
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
authors.forename: Ginji
authors.initials: G
authors.lastname: Endo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001152:Arsenicals / Q000737:chemistry / Q000378:metabolism; D002101:Cacodylic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D005098:Exotoxins / Q000737:chemistry / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013457:Sulfur Compounds / Q000652:urine*; D013482:Superoxide Dismutase / Q000494:pharmacology
chemical_list: D001152:Arsenicals; D005098:Exotoxins; D013457:Sulfur Compounds; C472511:dimethylarsinous acid; D002101:Cacodylic Acid; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D003545:Cysteine; C009572:trimethylarsine