Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9017836 | Toxicology and Applied Pharmacology | 2005 | 12 Pages |
Abstract
Human pentavalent arsenic metabolic intermediate, monomethylarsonic acid (MMAsV), is a major arsenic type found in the blood in chronic arsenic poisoning patients, but little information is available on its toxicity potential or mechanisms of action. In this study, we investigated the molecular mechanisms of in vitro cytolethality of MMAsV using rat liver TRL 1215 cells. Cellular arsenic concentrations reached the nanomolar range in TRL 1215 cells when cells were exposed to millimolar levels of MMAsV, and most of the MMAsV was not metabolized during the 48-h incubation. Under these conditions, MMAsV showed significant cytolethality when cellular reserves of reduced glutathione (GSH) were depleted. Morphological and biochemical evidence confirmed that MMAsV induced both necrosis and apoptosis in the cellular GSH-depleted cells. MMAsV significantly enhanced cellular caspase 3 activity in the cellular GSH-depleted cells, and a caspase 3 inhibitor blocked MMAsV-induced apoptosis. MMAsV also enhanced the production of cellular reactive oxygen species (ROS) in the cellular GSH-depleted cells, and addition of a membrane-permeable radical trapping reagent completely prevented both MMAsV-induced cellular caspase 3 activation and cytolethality in these cells. These observations suggest that MMAsV typically generates harmful ROS in cells, and cellular GSH prevents cytolethality by scavenging these toxic ROS. However, when cellular GSH levels are decreased, MMAsV induces oxidative stress in the cells, and this leads to apoptosis and/or necrosis depending on the cellular ROS/GSH ratio.
Keywords
DCFH-DAl-buthionine (S,R)-sulfoximineICP MSZ-DEVD-FMKTdTBSOGSHDMPOAAS2′,7′-dichlorofluorescein diacetateROSArsenicAtomic absorption spectrophotometrydimethylarsinic acidmonomethylarsonic acidTdT-mediated dUTP nick end labelingTUNELApoptosisPropidium iodidereduced glutathionehigh performance liquid chromatographyHPLCGlutathioneReactive oxygen species
Related Topics
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Authors
Teruaki Sakurai, Masayuki Ochiai, Chikara Kojima, Takami Ohta, Masumi H. Sakurai, Naoko O. Takada, Wei Qu, Michael P. Waalkes, Seiichiro Himeno, Kitao Fujiwara,