Nitric oxide toxicity in islet cells involves poly(ADP-ribose) polymerase activation and concomitant NAD+ depletion.
Previous studies have shown that DNA strand breaks are an early consequence of nitric oxide toxicity in pancreatic islet cells. We show here that exposure of islet cells to chemical NO donors causes the formation of ADP-ribose polymers in cell nuclei, with concomitant depletion of intracellular NAD+. Islet cell lysis was largely prevented by the ADP-ribosylation inhibitors nicotinamide, 3-aminobenzamide, and 4-amino-1,8-naphthalimide, the latter being a potent new-generation compound with high selectivity for poly(ADP-ribosyl)-ation. These findings indicate a key role of poly(ADP-ribose) polymerase activation in NO toxicity in islet cells.
Radons
J
J
Diabetes Research Institute, University of Düsseldorf, Germany.
Heller
B
B
Bürkle
A
A
Hartmann
B
B
Rodriguez
M L
ML
Kröncke
K D
KD
Burkart
V
V
Kolb
H
H
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004789:Enzyme Activation; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D009243:NAD / Q000378:metabolism*; D053644:Naphthalimides; D009536:Niacinamide / Q000494:pharmacology; D009569:Nitric Oxide / Q000633:toxicity*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors
D001549:Benzamides; D053644:Naphthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; D009243:NAD; C086538:4-amino-1,8-naphthalimide; D009536:Niacinamide; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; C025160:3-aminobenzamide; D015057:1-Naphthylamine; D011065:Poly(ADP-ribose) Polymerases; D010396:Penicillamine