Dimethylarsinic acid causes apoptosis in HL-60 cells via interaction with glutathione.
Inducibility of apoptosis in cultured human HL-60 cells by arsenic compounds, such as arsenite, arsenate, methylarsonic acid (MAA), and dimethylarsinic acid (DMAA), was investigated, together with the role of glutathione (GSH) in the induction. Among the arsenic compounds DMAA was the most potent in terms of the ability to cause the morphological changes (formation of nuclear fragmentation and apoptotic bodies) characteristic of apoptosis. Furthermore, fragmentation of internucleosomal DNA was also induced by DMAA. Depletion of cell GSH by L-buthionine-SR-sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase, enhanced the cytotoxicity of arsenite, arsenate, and MAA, while such depletion suppressed the cytotoxicity of DMAA. The depletion of GSH also suppressed the morphological changes and the fragmentation of internucleosomal DNA caused by DMAA, both of which are characteristic features of apoptosis. The results suggest that the death of cells caused by DMAA is due to apoptosis and that GSH is involved in the induction of apoptosis by this arsenic compound.
Department of Environmental Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan.
T
T
Ochi
F
F
Nakajima
T
T
Sakurai
T
T
Kaise
Y
Y
Oya-Ohta
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001149:Arsenates / Q000633:toxicity; D020261:Arsenic Poisoning; D001152:Arsenicals; D018053:Arsenites / Q000633:toxicity; D002101:Cacodylic Acid / Q000633:toxicity*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects*; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D009707:Nucleosomes / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity*
D001149:Arsenates; D001152:Arsenicals; D018053:Arsenites; D006540:Herbicides; D009707:Nucleosomes; D013723:Teratogens; D002101:Cacodylic Acid; D005978:Glutathione; C020300:monomethylarsonic acid; C015001:arsenite; C025657:arsenic acid