title: Glutathione plays a role in regulating the formation of toxic reactive intermediates from diphenylarsinic acid.
abstract: The role of glutathione (GSH) in the cytotoxicity of diphenylarsinic acid [DPAA(V)], which was detected in drinking well water after a poisoning incident in Kamisu, Japan, was investigated in cultured human HepG2 cells. DPA-GS(III), which is the GSH adduct of DPAA, was synthesized and analyzed by HPLC/ESI-MS. DPA-GS(III) was highly toxic to cells and the potency was about 1000 times that of DPAA(V). DPAA(V) was stable in culture medium, while DPA-GS(III) was unstable and changed to protein-bound As (protein-As). By contrast, DPA-GS(III) remained stable with the addition of exogenous GSH, thereby reducing transformation to protein-As. In addition, DPA-GS(III) was transformed to bis(diphenylarsine)oxide [BDPAO(III)], which was observed under serum-free conditions. BDPAO(III) was very unstable and disappeared conversely with an increase in protein-As. In contrast, the presence of GSH suppressed the transformation of BDPAO(III) to protein-As while it enhanced the transformation of BDPAO(III) to DPA-GS(III). Depletion of cell GSH enhanced the cytotoxic effects of DPA-GS(III) and BDPAO(III). Moreover, exogenously-added GSH suppressed the cytotoxic effects of DPA-GS(III) and BDPAO(III). The dynamic behavior of arsenicals in the culture medium and the resultant cytotoxic effects suggested that GSH played a role in regulating the formation of toxic intermediates, such as DPA-GS(III) and BDPAO(III). Moreover, the results suggested that the formation of protein-As in culture medium was compatible with the cytotoxic effects and that GSH was a factor capable of regulating the formation of protein-As from either DPA-GS(III) or BDPAO(III).
authors.affiliation: Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ochi
authors.forename: Toshihide
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kita
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kaise
mesh_terms: D020261:Arsenic Poisoning / Q000378:metabolism*; D001152:Arsenicals / Q000032:analysis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002619:Chemical Warfare Agents / Q000032:analysis / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D001152:Arsenicals; D002619:Chemical Warfare Agents; D005978:Glutathione; C493087:diphenylarsinic acid