Ultimate carcinogenetic compound of arsenic : the chemical structure and the toxicity

• Project/Area Number: 15590518
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hygiene
• Research Institution: Koshien University (2004); Osaka City University (2003)
• Principal Investigator: YOSHIDA Kaoru Koshien University, College of Nutrition, Associate Professor, 栄養学部, 助教授 (10336787)
• Co-Investigator(Kenkyū-buntansha): ENDO Ginji Osaka City University, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (20160393) ; KURODA Koichi Osaka City University, Graduate School of Medicine, Associate Professor, 大学院・医学研究科, 助教授 (30158886)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
• Keywords: arsenic / E.coli / metabolism / intestinal bacteria / cysteine / LC-ICP-MS / LC-MS / cytotoxicity

Research Abstract

Our previous study revealed that unidentified metabolites, M1, M2, and M3, were detected in urine and feces after long-term oral administration of dimethylarsinic acid (DMAV) to rats. In addition, we reported that the E.coli A3-6 converted DMAV to M-2 and M-3 and converted Trimethylarsine oxide (TMAO) to M1, and the conversion of DMAV to M2 and M-3 by E.coli A3-6 required cysteine (Cys). In this study we examined the mechanism of production of these unknown metabolites in vitro and in vivo. In vitro study, DMAV was converted to M2 and further to M3 in the presence of Cys and A3-6. TMAO was rapidly converted to M1. The maximum concentration of M2 was observed at a Cys/DMA ratio of 2, and the maximum of M3 was observed when the ratio exceeded 3. In vivo experiment, the results indicated that dietary Cys and E.coli affected the production of M2 and M3. In addition, we examined the chemical properties of M-2 by LC-ICP-MS and LC/MS. M2 was oxidized to DMAV by hydrogen peroxide, suggesting that M2 may be a DMA complex. M2 was consistent with the reactant of DMAV with metabisulfite-thiosulfate reagent. The molecular weight of M-2 was 154 and M-2 was a sulfur-containing metabolite.
The cytotoxicity of the unidentified metabolites was investigated. M2 was more cytotoxic than DMAV, M1, and M3 in V79 cells. Cytotoxicity of M2 in HL-60 cells was decreased by the addition of superoxide dismutase, suggesting that the cytotoxicity of M2 might be due to the production of reactive oxygen species.

Research Products

• [Journal Article] Genotoxicity of dimethylarsinous acid ; high induction of tetraploid. (2005)
  • Author(s): Kuroda, K., Yoshida, K., Yoshimura, M., Endo, Y., Endo, Y., Wanibuchi, H., Fukushima, S., Endo, G.
  • Journal Title: Appl.Organomet.Chem 19 Pages: 221-225
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genotoxicity of dimethylarsinous acid ; high induction of tetraploid. (2005)
  • Author(s): Kuroda, K., Yoshida, K., Yoshimura, M., Endo, Y., Endo, Y., Wanibuchi, H., Fukushima, S., Endo, G.
  • Journal Title: Appl.Organomet.Chem. 19 Pages: 221-225
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genotoxicity of dimethylarsinous acid ; high induction of tetraploid. (2005)
  • Author(s): Kuroda, K., Yoshida, K., Yoshimura, M., Endo, Y., Endo, Y., Wanibuchi, H., Fukushima, S., Endo, G..
  • Journal Title: Appl.Organomet.Chem 19 Pages: 221-225
• [Journal Article] Determination of trivalent methylated arsenicals in rat urine by liquid chromatography-inductively coupled plasma mass spectrometry after solver extraction. (2004)
  • Author(s): Okina, M., Yoshida, K., Kuroda, K., Wanibuchi, H., Fukushima, S., Endo, G.
  • Journal Title: J.Chromatogr.B 799 Pages: 209-215
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 食餌中のシステインおよび腸内細菌がヒ素の代謝に与える影響 (2004)
  • Author(s): 吉田 香, 翁 昌子, 北村真理, 周 栩, 鰐渕 英機, 圓藤吟史, 黒田孝一
  • Journal Title: 生活衛生 48・1 Pages: 407-414
  • NAID: 130004809609
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Microbial metabolite of dimethylarsinic acid is highly toxic and genotoxic. (2004)
  • Author(s): Kuroda, K., Yoshida, K., Yoshimura, M., Endo, Y., Endo, G.
  • Journal Title: Toxicol.Appl.Pharmacol. 198 Pages: 345-353
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Understanding arsenic carcinogenicity by the use of animal models. (2004)
  • Author(s): Wanibuchi, H., Salim, E.I., Kinoshita, A., Shen, J., Wei, M., Morimura, K., Yoshida, K., Kuroda, K., Endo, G., Fukushima, S.
  • Journal Title: Toxicol.Appl.Pharmacol. 198 Pages: 366-376
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Determination of trivalent methylated arsenicals in rat urine by liquid chromatography-inductively coupled plasma mass spectrometry after solvent extraction. (2004)
  • Author(s): Okina, M., Yoshida, K.Kuroda, K., Wanibuchi, H., Fukushima, S., Endo, G.
  • Journal Title: Chromatogr.B. 799 Pages: 209-215
  • NAID: 10016546419
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of dietary cysteine and enteromoicroorgnisms on the metabolism of arsenic. (2004)
  • Author(s): Yoshida, K., Okina, M., Kitamura, M., Zhou, X., Wanibuchi, H., Endo, G., Kuroda, K.
  • Journal Title: Seikatsu Eisei 48 Pages: 407-414
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Understanding arsenic carcinogenicity by the use of animal models. (2004)
  • Author(s): Wanibuchi, H., Salim, E.I., Kinoshita, A., Shen.J., Wei, M., Morimura, K., Yoshida, K., Kuroda, K., Endo, G., Fukushima, S.
  • Journal Title: Toxicol.Appl.Pharmacol. 198 Pages: 366-376
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Determination of trivalent methylated arsenicals in rat urine by liquid chromatography-inductively coupled plasma mass spectrometry after solvent extraction. (2004)
  • Author(s): Okina, M., Yoshida, K., Kuroda, K., Wanibuchi, H., Fukushima, S., Emdo, G.
  • Journal Title: J.Chromatogr.B 799 Pages: 209-215
  • NAID: 10016546419
• [Journal Article] 食餌中のシステインおよび腸内細菌がヒ素の代謝に与える影響 (2004)
  • Author(s): 吉田 香, 翁 昌子, 北村真理, 周 栩, 鰐渕英機, 圓藤吟史, 黒田孝一
  • Journal Title: 生活衛生 48・1 Pages: 407-414
  • NAID: 130004809609
• [Journal Article] Understanding arsenic carcinogenicity by the use of animal models. (2004)
  • Author(s): Wanibuchi, H., Salim, E.I., Kinoshita, A., Shen.J., Wei, M., Morimura, K., Yoshida, K., Kuroda, K., Endo, G., Fukushima
  • Journal Title: Toxicol.Appl.Pharmacol. 198 Pages: 366-376
• [Journal Article] Effects of cysteine on the cytotoxicity of arsenic compounds. (2003)
  • Author(s): Zhou, X., Yoshida, K., Kuroda, K., Endo, Y., Endo, G.
  • Journal Title: Arch.Environ.Contam.Toxcol. 45 Pages: 324-330
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Urinary sulfur-containing metabolite produced by intestinal bacteria following oral administration of dimethylarsinic acid to rats. (2003)
  • Author(s): Yoshida, K., Kuroda, K., Zhou, X., Inoue, Y., Date, Y., Wanibuchi, H., Fukushima, S., Endo, G.
  • Journal Title: Chem.Res.Toxicol. 16・9 Pages: 1124-1129
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of cysteine on the cytotoxicity of arsenic compounds. (2003)
  • Author(s): Zhou, X., Yoshida, K., Kuroda, K., Endo, Y., Endo, G.
  • Journal Title: Arch.Environ.Contain.Toxcol 45 Pages: 324-330
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Urinary sulfur-containing metabolite produced by intestinal bacteria following oral administration of dimethylarsinic acid to rats. (2003)
  • Author(s): Yoshida, K., Kuroda, K., Zhou, X., Inoue, Y., Date, Y., Wanibuchi, H., Fukushima, S., Endo, G.
  • Journal Title: Chem.Res.Toxicol. 16 Pages: 1124-1129
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Zhou, X., Yoshida, K., Kuroda, K., Endo, Y., Endo, G.: "Effects of cysteine on the cytotoxicity of arsenic compounds"Arch.Environ.Contam.Toxcol.. 45. 324-330 (2003)
• [Publications] Yoshida, K., Kuroda, K., Zhou, X., Inoue, K., Date, Y., Wanibuchi, H., Fukushima, S., Endo, G.: "Urinary sulfur-containing metabolite produced by intestinal bacteria following oral administration of dimethylarsinic acid to rats"Chem.Res.Toxicol.. 16・9. 1124-1129 (2003)