title: Pharmacodynamics of S-dimethylarsino-glutathione, a putative metabolic intermediate of inorganic arsenic, in mice.
abstract: Inorganic arsenicals are well-known carcinogens, whereas arsenite (iAsIII) compounds are now recognized as potent therapeutic agents for several leukemias, and arsenic trioxide has been used for the treatment of recurrent acute promyelocytic leukemia (APL). However, recent clinical trials revealed that arsenite is not always effective for non-APL malignancies. Another arsenical, S-dimethylarsino-glutathione ([DMAIII(GS)]), which is a putative metabolic intermediate in the hepatic metabolism of iAsIII, shows promise for treating several types of lymphoma. However, the metabolism of [DMAIII(GS)] has not been well investigated, probably because [DMAIII(GS)] is not stable in biological fluids where the concentration of glutathione is low. In the present study, we injected [DMAIII(GS)] intravenously into mice and compared the tissue distribution and metabolic dynamics of [DMAIII(GS)] with those of sodium arsenite (NaAsO2). We found a unique organ preference for the distribution of [DMAIII(GS)] to the lung and brain in comparison to NaAsO2. Furthermore, [DMAIII(GS)] appeared to bind to serum albumin by exchanging its glutathione moiety quickly after administration, providing novel insights into the longer retention of [DMAIII(GS)] in plasma.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Japan; Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kato
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Japan; Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Udagawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Japan; Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Japan. Electronic address: seishiro@nies.go.jp.
authors.forename: Seishiro
authors.initials: S
authors.lastname: Hirano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001152:Arsenicals / Q000097:blood / Q000493:pharmacokinetics*; D018053:Arsenites / Q000493:pharmacokinetics*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D017670:Sodium Compounds / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D018053:Arsenites; D012709:Serum Albumin; D017670:Sodium Compounds; C017947:sodium arsenite; C515055:darinaparsin; D005978:Glutathione
keywords: Albumin; Arsenite; HPLC-ICP-MS; S-dimethylarsino-glutathione; Tissue distribution