Cytotoxicity of peroxynitrite in rat pancreatic acinar AR4-2J cells.
Peroxynitrite (0.5-50 microM) induced dose-dependent cytotoxic effects in rat pancreatic acinar AR4-2J cells. Glutathione (2 mM) and ebselen (10 microM) partially reduced the cytotoxicity caused by 1-10 microM concentrations of peroxynitrite. Higher concentrations (10-50 microM) of peroxynitrite induced DNA smear suggestive of necrosis, while lower concentrations (2-5 microM) induced DNA fragmentations suggestive of apoptosis. The effects of peroxynitrite on [Ca2+]i showed a similar dose dependency. Peroxynitrite concentrations > 10 microM rapidly increased [Ca2+]i in a dose-dependent manner, while concentrations < 5 microM did not affect [Ca2+]i. In contrast, the presentation of wild-type P53 was accelerated at lower concentrations of peroxynitrite (< or = 10 microM) but not at higher concentrations (50 microM). The present study suggests that peroxynitrite at lower concentrations (2-5 microM) induces wildtype P53 and apoptosis, which is potentially a protective response toward the DNA damage caused by peroxynitrite. On the other hand, higher concentrations of peroxynitrite (10-50 microM) rapidly increase [Ca2+]i and eventually induce necrosis.
Sata
N
N
Department of Gastroenterology, University of Düsseldorf, Germany.
Klonowski-Stumpe
H
H
Han
B
B
Häussinger
D
D
Niederau
C
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001393:Azoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D016158:Genes, p53; D005978:Glutathione / Q000494:pharmacology; D054833:Isoindoles; D009154:Mutation; D009336:Necrosis; D009566:Nitrates / Q000008:administration & dosage / Q000633:toxicity*; D016566:Organoselenium Compounds / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000139:chemically induced; D051381:Rats; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D009566:Nitrates; D016566:Organoselenium Compounds; C039642:peroxynitric acid; C042986:ebselen; D005978:Glutathione; D002118:Calcium