The role of glutathione on the cytotoxic effects and cellular uptake of diphenylarsinic acid, a degradation product of chemical warfare agents.
The mechanism underlying enhancement of the cytotoxic effects of diphenylarsinic acid (DPAA) by sulfhydryl (SH) compounds, such as glutathione (GSH) and dimercaptopropane sulfonate (DMPS), was investigated in terms of not only the effects of SH compounds on DPAA uptake by cells, but also the cytotoxic effects of the GSH adduct of DPAA, DPA-GS. In addition, the cytotoxic effects of DPA-GS and cellular uptake were investigated in conjunction with the effects of GSH depletion. Cells took up DPAA in a time- and temperature-dependent manner for up to 2 h, then the uptake leveled off for 6 h. Arsenic species other than DPAA were not detected in the cells. The presence of GSH and DMPS did not influence the rate of uptake of DPAA by the cells. By contrast, when the cytotoxic potential of DPA-GS was compared with that of DPAA, DPA-GS was about 1,000 times more toxic than DPAA, suggesting that enhancement of DPAA toxicity by SH compounds might be due to the formation of adducts in the culture medium. The cytotoxic effects of DPA-GS were suppressed markedly by the presence of GSH and DMPS, and the suppression was attributed to an inhibition of more than 90% by the SH compounds of DPA-GS uptake. Depletion of cell GSH enhanced the cytotoxic effects of DPA-GS by two to three times and the enhancement attributed to an increased cellular uptake of DPA-GS. These results suggest that GSH plays a role in regulating the formation of DPA-GS and cellular uptake.
Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, 199-0195 Sagamiko Kanagawa, Japan. tkfmochi@pharm.teikyo-u.ac.jp
Takafumi
T
Ochi
Kenji
K
Kinoshita
Toshihide
T
Suzuki
Kouichi
K
Miyazaki
Ayano
A
Noguchi
Toshikazu
T
Kaise
D001152:Arsenicals / Q000009:adverse effects* / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000378:metabolism* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D013058:Mass Spectrometry
D001152:Arsenicals; D002619:Chemical Warfare Agents; D005978:Glutathione; C493087:diphenylarsinic acid