Arsenic trioxide and lead acetate induce apoptosis in adult rat hepatic stem cells.
In the present study, the toxicity of arsenic trioxide and lead acetate was assessed in adult hepatic stem cells induced in the 2-acetyl-aminofluorene/partial hepatectomy rat model. Isolated oval cells were incubated separately for 6 h with 40 muM each of arsenic trioxide and lead acetate. 3-(4,5-Dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay denoted significant time-dependent cell death in arsenic and lead treated oval cells. The degree of stress imposed by these metals was evidenced by induction of heat shock protein (HSP) 70 and HSP 90. Arsenic and lead were found to trigger apoptosis as revealed by DNA ladder formation, Western blots of apoptotic factors, and reverse transcriptase polymerase chain reaction analyses of bax and bcl-2. Results clearly indicate that both arsenic and lead induced apoptosis is caspase-mediated and accompanied by extracellular signal-regulated kinase (ERK) dephosphorylation. Full-length BH3-interacting-domain death agonist expression in presence of caspase 3 inhibitor unravels a direct involvement of caspase in As and Pb induced apoptosis. Expression patterns of apoptosis inducing factor, B cell lymphoma-2 (Bcl-2) antagonist of cell death, Bcl-2-associated X protein, and Bcl2 also signify mitochondrial regulation of apoptosis effected by lead and arsenic. It is concluded that stimulation of caspase cascade and simultaneous ERK dephosphorylation are the most significant operative pathways directly associated with apoptotic signals triggered by arsenic and lead in the oval cells.
Agarwal
Soumik
S
Environmental Toxicology Laboratory, Department of Zoology, Visva-Bharati University, Santiniketan 731235, India.
Roy
Sonali
S
Ray
Atish
A
Mazumder
Shibnath
S
Bhattacharya
Shelley
S
D000818:Animals; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D008099:Liver / Q000166:cytology*; D008297:Male; D009942:Organometallic Compounds / Q000633:toxicity*; D010087:Oxides / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology
D001152:Arsenicals; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D009942:Organometallic Compounds; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D048049:Extracellular Signal-Regulated MAP Kinases; C008261:lead acetate; D000077237:Arsenic Trioxide